HODJKIN’S LYMPHOMA Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

Hodgkin’s lymphoma is a malignant disease that affects the lymphatic system. In the majority of cases the neoplastic cells can be derived from B lymphocytes. Characteristic feature is a low number of malignant Hodgkin-Reed-Sternberg (H-RS) cells surrounded by numerous reactive cells (bystander cells). Most common primary localizations are cervical (60- 80%), mediastinal, and inguinal lymph nodes. Hodgkin’s lymphomas disseminate both via lymphatic vessels or per continuitatem into lymphatic organs as well as by blood vessels or per continuitatem into extralymphatic organs. Hodgkin’s Lymphoma

Epidemiology The incidence rate is at 2-3/100,000 per year. The age peak lies at approx. 32 years. Hodgkin lymphoma is one of the most treatable forms of cancer. About 75 percent of people diagnosed with Hodgkin lymphoma can be cured with treatment. Over 90 percent of people live at least 10 years after treatment. Hodgkin’s Lymphoma

Classification of Hodgkin’s lymphomas is according to the WHO classification: I. Nodular Lymphocyte-predominant Hodgkin’s lymphoma (NLPHL) The NLPHL encompasses almost 5% of all Hodgkin’s lymphomas. As opposed to the classical Hodgkin’s lymphomas the malignant cells are referred to as L&H (lymphocytic and histiocytic) and most often display the B-cell antigens CD20 and CD79a. For therapeutic purposes, nodular lymphocyte- predominant HL is managed in the same way as indolent non-Hodgkin lymphoma Classification

II. Classical Hodgkin’s lymphoma (cHL) Nodular sclerosing (NS) Mixed cellularity (MC) Lymphocyte-rich (LR) Lymphocyte-depleted (LD) Not classified Tumor cells of the classical Hodgkin’s lymphomas are referred to as Hodgkin and Reed-Sternberg cells (H-RS) and typically display CD30 and CD15 antigens. Stage-adapted therapy allows long term cure in more than 80 percent of all patients. Hodgkin’s lymphoma is one of the oncological diseases with the highest cure rates in adults Classification

Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of patients) Constitutional symptoms (eg, unexplained weight loss [>10% of total body weight], unexplained fever, night sweats) are present in 40% of patients; collectively, these are known as "B symptoms" Intermittent fever is observed in approximately 35% of cases; infrequently, the classic Pel-Ebstein fever is observed (high fever for 1-2 wk, followed by an afebrile period of 1-2 wk) Features of Hodgkin lymphoma include:

Chest pain, cough, SOB, or a combination of those may be present due to a large mediastinal mass or lung involvement; rarely, hemoptysis occurs Pain at sites of nodal disease, precipitated by drinking alcohol, occurs in fewer than 10% of patients but is specific for Hodgkin lymphoma Back or bone pain rarely occur May present with pruritus A family history is also helpful; in particular, nodular sclerosis Hodgkin lymphoma (NSHL) has a strong genetic component and has often previously been diagnosed in the family Features of Hodgkin lymphoma include:

Physical examination include: Painless lymphadenopathy can be seen in the cervical area (neck, 60-80%), axilla (armpit, 6-20%), and, less commonly, in the inguinal area (groin, 6-20%) Waldeyer ring (back of the throat, including the tonsils) or occipital (lower rear of the head) or epitrochlear areas is infrequently observed Splenomegaly and/or hepatomegaly may be present Superior vena cava syndrome may develop in patients with mediastinal lymphadenopathy CNS symptoms or signs may be due to paraneoplastic syndromes, including: Cerebellar degeneration, neuropathy Guillain-Barre syndrome Multifocal leukoencephalopathy Physical Examination

Any disease presenting with lymphadenopathy and constitutional symptoms Infection with human (HIV) immunodeficiency virus Hypersensitivity reaction Other solid tumors Non-Hodgkin lymphoma, particularly diffuse large B cell lymphoma and anaplastic large cell lymphoma, both of which may have CD30 expression Failure to diagnose the disease in a timely manner, possibly due to the following factors The misinterpretation of B symptoms A lack of follow-up for abnormal chest radiographs or physical examination findings A missed pathologic diagnosis because a needle biopsy was obtained rather than an excisional lymph node biopsy Diagnostic considerations

Occasionally, Hodgkin lymphoma can present as hemophagocytic syndrome (hemophagocytic lymphohistiocytosis). The hemophagocytic syndrome may be more prevalent in patients with Epstein-Barr virus (EBV) antigen expression and has the following characteristics: Pancytopenia Fever Hepatosplenomegaly with liver function test abnormalities Elevated serum levels of ferritin and triglycerides Phagocytosis of hematopoietic lineage cells by benign macrophages Diagnostic considerations

Cytomegalovirus Infectious Mononucleosis Non-Hodgkin Lymphoma Systemic Lupus Erythematosus Sarcoidosis Serum Sickness Small Cell Lung Cancer Syphilis Toxoplasmosis Tuberculosis Differential Diagnoses

Diagnosis TestComments Case historyB symptoms Fever Night sweats (change of night clothes) Unintentional weight loss (< 10% of body weight within 6 months) Physical examination Palpable lymph nodes Hepatosplenomegaly Laboratory analyses Complete blood cell count, including leukocyte count with differential Erythrocyte sedimentation rate LDH, GOT, GPT, AP, Gamma GT, uric acid, creatinine Imaging Chest X-rays CT scan of the neck (with contrast medium) CT scan of the chest (with contrast medium) CT scan of the abdomen (with contrast medium) Bone-marrow puncture Aspirate (cytology) Biopsy (histology)

Stage IInvolvement of a single lymph node region (I,N) or involvement of a single or localized extranodal site (I,E) Stage IIInvolvement of two or more lymph node regions on the same side of the diaphragm or involvement of an extra-nodal site or organ and one or more lymph node regions on the same side of the diaphragm Stadium IIIInvolvement of two or more lymph regions and/or organs outside the lymphatic system on both sides of the diaphragm Stadium IVNon-localized, diffuse or disseminated involvement of one or several extra-lymphatic organs with or without involvement of lymphatic tissues. Addendum ANo B symptoms Addendum BPresence of B symptoms Staging according to Ann Arbor Classification

Nodular sclerosing Hodgkin lymphoma of the mediastinum. The diagnosis is strongly suggested by the presence of distinct nodules on the cut surface of this lymph node. Very high magnification micrograph of NLPHL, with a popcorn-shaped Reed-Sternberg cell (hematoxylin and eosin).

Micrograph of Hodgkin lymphoma in a fine-needle aspiration lymph node specimen (field stain). Eosinophils, Reed-Sternberg cells, plasma cells, and histocytes can be seen.

Unfavorable Risk Factors for Stages I and II Hodgkin Lymphoma Risk FactorGSHGEORTCNCIC Age ≥ 50y≥ 40y Histology MC or LD ESR or B symptoms> 50 if A or > 30 if B > 50 or any B symptoms Mediastinal mass*MMR > 0.33MMR > 0.35 MMR > 0.33 or > 10 cm Number of nodal sites > 2> 3 Mediastinal mass is measured on chest x-ray by the mediastinal mass ratio (MMR), which is defined by the following: maximum width of mass/maximum\ intra-thoracic diameter. ESR = erythrocyte sedimentation rate; LD = lymphocyte depletion; MC = mixed cellularity.

This image depicts a computed tomography (CT) scan, positron- emission tomography (PET) scan, and maximum intensity projection (MIP) PET scan from a patient with histologically proven Hodgkin lymphoma.

Non-Hodgkin lymphomas (NHLs) are tumors originating from lymphoid tissues, mainly of lymph nodes. These tumors may result from chromosomal translocations, infections, environmental factors, immunodeficiency states, and chronic inflammation Signs and symptoms Peripheral adenopathy: Painless and slowly progressive; can spontaneously regress Primary extranodal involvement and B symptoms: Uncommon at presentation; however, common with advanced, malignant transformation or end-stage disease Bone marrow: Frequent involvement; may be associated with cytopenias(s); fatigue weakness more common in advanced-stage disease Non-Hodgkin lymphomas (NHLs)

Signs and symptoms Intermediate- and high- grade lymphomas have a more varied clinical presentation: Adenopathy: Most patients Extranodal involvement: More than one third of patients; most common sites are GI/GU tracts (including Waldeyer ring), skin, bone marrow, sinuses, thyroid, CNS B symptoms: Temperature >38°C, night sweats, weight loss >10% from baseline within 6 months; in approximately 30-40% of patients Non-Hodgkin lymphomas (NHLs)

Examination in patients with low-grade lymphomas may demonstrate peripheral adenopathy, splenomegaly, and hepatomegaly. Intermediate- and high- grade lymphomas may result in the following examination findings Rapidly growing and bulky lymphadenopathy Splenomegaly Hepatomegaly Large abdominal mass: Usually in Burkitt lymphoma Testicular mass Skin lesions: Associated with Cutaneous T-cell lymphoma (mycosis fungoides) Anaplastic large-cell lymphoma, and Angioimmunoblastic lymphoma Physical Examination

Potential disease-related complications include: Cytopenias (ie, neutropenia, anemia, thrombocytopenia) autoimmune hemolytic anemia is observed in some NHL types Bleeding secondary to thrombocytopenia, DIC, or vascular invasion by the tumor Infection secondary to neutropenia Cardiac problems secondary to large pericardial effusion or arrhythmias secondary to cardiac metastases Respiratory problems secondary to pleural effusion and/or parenchymal lesions Superior vena cava (SVC) syndrome secondary to a large mediastinal tumor Spinal cord compression secondary to vertebral metastases Neurologic problems secondary to primary CNS lymphoma or lymphomatous meningitis GI obstruction, perforation, and bleeding in a patient with GI lymphoma (may also be caused by chemotherapy) Pain secondary to tumor invasion Leukocytosis (lymphocytosis) in leukemic phase of disease Complications

Laboratory studies with suspected NHL include: CBC count: May show anemia, thrombocytopenia leukopenia/pancytopenia, lymphocytosis, thrombocytosis Serum chemistry: May show elevated LDH, LFT and calcium levels Serum beta2-microglobulin level: May be elevated HIV serology: Especially in patients with diffuse large cell immunoblastic or small non cleaved histologies Human T-cell lymphotropic virus-1 serology: Patients with adult T-cell leukemia/lymphoma Hepatitis B testing: In patients in whom rituximab therapy is planned Immunophenotypic analysis of lymph node, bone marrow, peripheral blood Cytogenetic studies: NHL associated with monoclonal gammopathy; possible positive Coombs test; hypogammaglobulinemia Testing :

The imaging studies for NHL include: Chest radiography Upper GI series with small bowel follow-through: In patients with head and neck involvement and those with a GI primary lesion CT scanning of the neck, chest, abdomen, and pelvis PET scanning Bone scanning: Only in patients with bone pain, elevated alkaline phosphatase, or both Testicular U/S: For opposite testis in male patients with a testicular primary lesion Multiple gated acquisition scanning: For patients being considered for treatment with anthracyclines MRI of brain/spinal cord: For suspected primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma Imaging:

The diagnosis of NHL relies on pathologic confirmation following appropriate tissue biopsy. The following are procedures in cases of suspected NHL: Bone marrow aspiration and biopsy: For staging rather than diagnostic purposes Excisional lymph node biopsy (extranodal biopsy): For lymphoma protocol studies Lumbar puncture for CSF analysis in patients with: Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, or nasopharyngeal involvement, or 2 or more extranodal sites of disease High-grade lymphoblastic lymphoma High-grade small non- cleaved cell lymphomas HIV-related lymphoma Primary CNS lymphoma Neurologic signs and symptoms Procedures:

The treatment of NHL varies greatly and include: Chemotherapy: Most common; usually combination regimens Radiation therapy Rituximab administration Bone marrow transplantation: Possible role in relapsed high-risk disease Radioimmunotherapy Transfusions of blood products Antibiotic Pharmacotherapy Medications include: Cytotoxic agents Histone deacetylase inhibitors (eg, vorinostat) Colony-stimulating factor (eg, epoetin filgrastim) Monoclonal antibodies (eg, rituximab, ibritumomab) Proteasome inhibitors (eg, bortezomib) Immunomodulators (eg, interferon alfa-2a or alfa-2b) Corticosteroids (prednisone, dexamethasone, Management:

Posteroanterior (PA) chest radiograph in a man with thoracic non-Hodgkin lymphoma (NHL) shows mediastinal widening due to grossly enlarged right paratracheal and left paratracheal nodes. A computed tomography (CT) scan showing bulk disease in a patient with Hodgkin lymphoma.

This 28-year-old man was being evaluated for fever of unknown origin. Gallium-67 study shows extensive uptake in the mediastinal lymph nodes due to non-Hodgkin lymphoma (NHL). Ultrasound throat lymphadenopathy non-hodgkin-lymphoma