LYMPHOMA: AN UPDATE FOR PHYSICIAN

LYMPHOMA: AN UPDATE FOR PHYSICIAN 10 : 1 Mammen Chandy, Vivek S Radhakrishnan, Kolkata The term lymphoma identifies a heterogeneous group of biologically and clinically distinct neoplasms that originate from the lymphoid organs and have historically been divided into two distinct categories, namely non Hodgkin s lymphoma (NHL) and Hodgkin s lymphoma (HL). 1,2 Based on biological, pathological and clinical criteria, there are more than 30 specific subtypes of Lymphoma. The subtypes are derived from B or T cells: the interested reader can review this in the recent WHO classification of lymphomas. 2 The NHLs and HL are the most commonly occurring hematologic malignancies in the United States. They now represent 4% to 5% of all new cancer cases and are the fifth leading cause of cancer death in the United States and the second fastest growing cancer in terms of mortality. NHL is the most common form and accounts for 88% of lymphoid tumors and HL accounts for 12% of cases. 3 Among children, lymphomas are the third most frequent malignancy, representing 15% of pediatric malignancies, with 1,700 new cases each year. Most cases of NHL are derived from the malignant transformation of B-Lymphocytes in lymph nodes. B-Cell lymphomas represent more than 85% of NHL. Follicular and Diffuse Large B Cell lymphomas (DLBCL) are the most frequent forms, each comprising around 30% of total cases. T-cell lymphomas account for less than 15% of NHL. 4 The following associations with infectious agents have been made with regard to the etiology of lymphomas; Human Immunodeficiency Virus 5 Epstein-Barr Virus 6 human T-cell lymphotropic virus type 1 (HTLV-1) 7 Human Herpesvirus-8 (HHV-8) 8 Hepatitis C Virus 9 Helicobater pylori 10 During the past 3 decades, significant progress has been made in elucidating the molecular pathogenesis of lymphoid malignancies as a clonal malignant expansion of B cells (in the majority of cases) or of T cells. The molecular characterization of the most frequent genetic abnormalities associated with lymphoma development has led to the identification of a number of proto-oncogenes and tumor suppressor genes that are altered in B-cell NHL (B-NHL) and whose abnormal functioning contributes to lymphoma pathogenesis. However relatively less is known about the pathogenesis of T-cell NHL (T-NHL) and HL. There are many articles which the reader can refer to which explain the molecular 11, 12 processes underlying B-cell Lymphomas and Nodal T-cell Lymphomas. Clinical features The clinical behavior of Lymphomas is diverse and ranges from highly malignant and rapidly growing tumors in people of all ages, to relatively benign and even non-progressive lymph node enlargement in 501

Medicine Update 2012 Vol. 22 elderly people. In NHL therefore simpler groupings are based on clinical behaviour and tend to be considered in two groups: Indolent Lymphomas (Low grade Lymphomas): e.g. Follicular Lymphoma, Marginal Zone Lymphoma Aggressive Lymphomas Intermediate grade: e.g. Diffuse Large B-Cell Lymphoma (DLBCL) High grade: e.g. Burkitt s lymphoma, Lymphoblastic Lymphoma Indolent lymphomas are characteristically diseases of older people (mainly men >50yrs), with a median untreated survival time measured in years. The aggressive lymphomas may present at any age but occur more frequently in the elderly. Although these forms are highly progressive, in contrast to indolent diseases, aggressive lymphomas, in many cases are curable with conventional therapy. Making a diagnosis of Lymphoma Lymphoma have been reported in most sites of the body (CNS, Gonads, skin, breast, bone included), as well as primary intravascular and effusion lymphomas, but most lymphomas arise within the lymphatic system. Patients may present with the following- Enlarged, usually painless lymphnodes anywhere in the body (commonly neck, axilla, or groin) ± splenomegaly ± hepatomegaly. Unexplained fever Night sweats Unintentional weight loss Less common but possible presentations may include Persistent fatigue Flu-like illness Generalised itching Abdominal pain Recurrent infections Anemia & other low blood counts Bone pain Shortness of breath/ protracted cough; and Neurologic symptoms Tissue Biopsy FNAC of the involved node is considered inadequate for diagnosing a lymphoma, and should not be performed. The only indication for FNAC is to exclude solid malignancies of the head or neck as a cause of Lymphadenopathy in the lateral neck, as an open biopsy may prejudice later definitive surgical management. In Lymphoma management, FNAC may have only a limited role in diagnosing a recurrence. Excision Biopsy of the involved and most prominent lymphnode is the Gold standard, even today, in the diagnosis of Lymphoma. Investigations to be carried out by a physician before referral to a specialist for a surgical biopsy include the following; Full blood count and peripheral blood smear Coagulation screen CXR Peripheral blood flow cytometry for immunophenotyping, if there is marked lymphocytosis USG of the enlarged lymphnode region Serology to rule out HIV, HBV, HCV viral infections Referral to a specialist or hospital for biopsy is urgent if there is evidence of any emergent complications of lymphoma including Spinal cord compression Pericardial tamponade SVC or IVC obstruction Airway obstruction Possible CNS mass lesions Intestinal obstruction Ureteric obstruction Severe Hepatic dysfunction Unwell patient When a pathological node is not readily accessible for open excision biopsy, such as with intra-abdominal disease, a Needle core biopsy is a reasonable initial procedure if open biopsy is not feasible. It is critical that the appropriate biopsy is performed by an experienced operator (to ensure a satisfactory sample is obtained), and interpreted or reviewed by a pathologist expert in hemato-pathology who can integrate the histological findings with the results of other investigations to arrive at a precise final diagnosis. A precise diagnosis is essential to avoid inappropriate treatment. In the clinic, a commonly encountered problem is the misdiagnosis of lymphoblastic lymphoma which requires treatment with intensive acute lymphoblastic leukemia like treatment protocol, unlike other lymphomas. Investigations apart from routine histopathology, which are essential for an accurate diagnosis, include 502

Lymphoma: An Update for Physician Table 1: WHO 2008: Classification of Lymphoid Neoplasms Mature B-cell neoplasms Burkitt lymphoma Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Hodgkin Lymphoma Splenic lymphoma/leukemia, unclassifiable Nodular lymphocyte-predominant Hodgkin lymphoma Splenic diffuse red pulp small B-cell lymphoma* Classical Hodgkin lymphoma Hairy cell leukemia-variant* Nodular sclerosis classical Hodgkin lymphoma Lymphoplasmacytic lymphoma Lymphocyte-rich classical Hodgkin lymphoma Waldenström macroglobulinemia Mixed cellularity classical Hodgkin lymphoma Heavy chain diseases Lymphocyte-depleted classical Hodgkin lymphoma Alpha heavy chain disease Mature T-cell and NK-cell neoplasms. Gamma heavy chain disease T-cell prolymphocytic leukemia Mu heavy chain disease T-cell large granular lymphocytic leukemia Plasma cell myeloma Chronic lymphoproliferative disorder of NK-cells Solitary plasmacytoma of bone Aggressive NK cell leukemia Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone B-cell lymphoma (MZL) Pediatric type nodal MZL Follicular lymphoma Pediatric type follicular lymphoma Primary cutaneous follicle center lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma (DLBCL), not otherwise specified T cell/histiocyte rich large B-cell lymphoma DLBCL associated with chronic inflammation Epstein-Barr virus (EBV) + DLBCL of the elderly Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary cutaneous DLBCL, leg type ALK+ large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Large B-cell lymphoma arising in HHV8-associated Multicentric Castleman disease B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma Systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection) Hydroa vacciniforme-like lymphoma Adult T-cell leukemia/ lymphoma Extranodal NK/T cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorder Lymphomatoid papulosis Primary cutaneous anaplastic large-cell lymphoma Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous small/medium CD4+ T-cell lymphoma Peripheral T-cell lymphoma, not otherwise specified Angioimmunoblastic T-cell lymphoma (AITL) Anaplastic large cell lymphoma (ALCL), ALK+ Anaplastic large cell lymphoma (ALCL), ALK Immunophenotyping (e.g. by Immuno-histochemistry), and cytogenetic studies like chromosomal analysis by Fluorescent In-Situ Hybridization (FISH) and other molecular methods. Staging Staging of lymphoma relies on Physical examination, Imaging modalities like X-rays, USG, CECT scans (of the Chest, Abdomen, Pelvis and sometimes of the neck), and Bone marrow aspiration and Biopsy. In a resource poor setting, staging may have to rely on inexpensive investigations like CXR-PA, USG-Whole Abdomen, etc. An evaluation of cerebrospinal fluid should be consid- 503

Medicine Update 2012 Vol. 22 ered in patients with diffuse large cell NHL with bone marrow involvement, a high LDH, or multiple extranodal sites of disease 13,14 as well as in patients presenting with epidural masses, testicular involvement, paranasal sinus, or nasopharyngeal involvement. A cerebrospinal fluid evaluation should be performed even in patients with high-grade lymphomas, such as lymphoblastic lymphoma or Burkitt lymphoma, and in patients with HIV-related lymphomas, primary CNS lymphomas, and post-transplantation lymphoproliferative disorders. A GI evaluation should be considered in patients with a known GI primary lymphoma or in patients with mantle cell lymphoma because of a high incidence of occult GI involvement. The stage of Lymphoma is categorized with the use of the Ann Arbor staging classification (Table 1). 15 This system is based on the distribution and number of involved sites, as well as the presence or absence of extranodal involvement and constitutional symptoms. Such symptoms include weight loss greater than 10% of body weight over the preceding 6 months, fever higher than 38 C unrelated to any infections, and drenching night sweats; which are labeled as B symptoms in the staging system. Role of Nuclear Imaging Nuclear medicine imaging with Whole body FDG PET- CT scan is assuming an increasingly important role in the management of lymphoma. It is being used in the following situations: pretreatment assessment, mid treatment evaluation of response, post-treatment restaging, Its impact on clinical outcome in most clinical situations remains to be confirmed. PET/CT provides its greatest clinical benefit in the post-treatment evaluation of HL and diffuse large B-cell lymphoma (DLBCL). 16 Prognostication Even within histological subtypes there is a wide range of disease outcomes, and factors that reliably predict the patient s response to therapy and eventual outcome are used as a standard for discussing prognosis, selecting therapy, and comparing results of clinical trials. The International Prognostic Index (IPI) was developed initially to categorize aggressive NHL on the basis of easily obtained clinical features that were independent predictors of survival. 17 Because younger and older patients may have different outcomes and younger patients may be considered for more aggressive therapies, an age-adjusted model for patients aged 60 years or younger also has been developed. The advent of targeted therapies, especially Rituximab for B-Cell NHL, influenced the devising of R-IPI (Revised-IPI) for aggressive B-cell NHL. 18 The IPI, which was essentially designed for aggressive lymphoma, may not clearly identify patients with indolent lymphoma and Mantle-cell Lymphoma who are at high risk; thus, new prognostic factor models have now been devised; e.g. the Follicular Lymphoma International Prognostic Index (FLIPI) 19 and the Mantle Cell international prognostic index (MIPI). 20 Treatment of Lymphomas Therapeutic modalities used commonly in the treatment of Lymphomas are Chemotherapy, and Radiation therapy (RT) Surgery, generally indicated for diagnosis of this disease, is seldom used as a therapeutic modality. A word of caution regarding evaluation of the patient: Initiating treatment prior to an accurate diagnosis, especially with steroids, can be counterproductive to patient care. This clinical scenario is commonly seen in the evaluation of a young patient presenting with a mediastinal mass and dyspnoea. Steroid therapy given prior to an accurate diagnosis can confound the results of a biopsy as it is capable of partially treating the disease, which leads to an erroneous diagnosis or no diagnosis at all. An extensive discussion on the management of specific lymphoma subtypes is beyond the scope of this article, we have thus restricted ourselves to the discussion of the following entities. Hodgkin Lymphoma For limited stage disease (Stage I & IIA): Two cycles of ABVD chemotherapy followed by involved-field radiotherapy (IF-RT) of 20 Gy is considered standard of care. 21 If an interim assessment with Whole body PET- CT shows complete response after 2 cycles, treatment can stop with 4 cycles of ABVD, without RT. For Intermediate stage (Early stage Unfavorable) patients: four cycles of ABVD followed by 30 Gy IF-RT is widely considered standard. 22 Advanced stage HL is usually treated with chemotherapy alone. Radiotherapy is confined to patients having large residual masses after chemotherapy. Patients up to 60 years old are treated with either six (patients with complete remission after four cycles) or eight (patients with partial remission after four cycles) cycles of ABVD or eight cycles of BEACOPP escalated. 23 Patients older than 60 years should be treated with 6 8 cycles (depending on the remission status after four cycles) of ABVD. 504

Lymphoma: An Update for Physician Table 2: Modified Ann Arbor Staging Classification of Non- Hodgkin Lymphoma Stage Description I Involvement of a single lymph node region I E Localized involvement of a single extra lymphatic organ or site II Involvement of 2 or more lymph node regions on the same side of the diaphragm II E Localized involvement of a single associated extralymphatic organ or site and its regional lymh nodes with or without other lymph node regions on the same side of the diaphragm III Involvement of lymph node regions on both sides of the diaphragm III E Involvement of lymph node regions on both sides of the diaphragm accompanied by localized involvement of an extralymphatic organ III 5 Involvement of lymph node regions on both sides of the diaphragm accompanied by involvemenht of the spleen III E-5 Involvement of lymph node regions on both sides of the diaphragm accompanied by both localized involvement of an extralymphatic organ or site and the spleen IV Disseminated (multifocal) involvement of 1 or more extralymphatic organs with or without associated lymph node involvement IV E Isolated extralymphatic organ involvement with distant (nonregional) nodal involvement Chemotherapy is followed by a localized radiation with 30 Gy to residual lymphoma >1.5 cm. Ongoing trials are aimed at reducing treatment intensity without compromising efficacy. Some trials suggest that interim FDG PET-CT is a good predictor for treatment 16, 24, 25 failure in patients with HL treated with ABVD. Hodgkin Lymphoma can occasionally present with unusual and non-metastatic manifestations which include icthyosiform atrophy, nephrotic syndrome (e.g Minimal Change Disease), paraneoplastic cerebellar degeneration, etc. Hodgkin Lymphoma can also be extremely immunosuppressive for the patient. An occasional patient may even die due to varicella infection, transfusion related Graft versus Host Disease, etc. It is well advised to practice transfusion only with Irradiated blood products in patients with Hodgkin Lymphoma requiring blood transfusions. NLPHL (Nodular Lymphocyte predominant Hodgkin Lymphoma) is treated identically to classic HL in all stages except for stage IA without risk factors, where a dose of 30 Gy IF-RT alone is the standard treatment. 26 In contrast to most chl cases, the malignant cells of NLPHL are characterized by a strong expression of CD20. Therefore, localized NLPHL relapses can be effectively treated with rituximab alone. 27 In patients with Relapsed or refractory HL, high-dose chemotherapy (e.g DHAP regimen) followed by autologous stem cell transplantation (ASCT) can be regarded as the treatment of choice. 28 The US FDA recently approved a new drug, Brentuximab Vedotin (SGN-35, Adcetris ), in patients whose disease has progressed after having received an autologous stem cell transplant, and in those ineligible for transplant who have failed at least 2 multiagent chemotherapy regimens. The product is a monoclonal (anti-cd 30) antibody drug conjugate. Follicular Lymphoma Limited non-bulky stage I II disease: In this small proportion of patients, radiotherapy (involved or extended field, 30 36 Gy) is the preferred treatment having a curative potential. 29 In selected cases a watchful waiting may be discussed to avoid the side effects of RT. 30 In patients with a large tumor burden or adverse prognostic features (high risk FLIPI), systemic therapy should be initiated. In the majority of patients with bulky, and advanced stage III and IV disease no curative therapy is yet established. Since the natural course of the disease is characterized by spontaneous regressions in up to 25% of cases and varies significantly from case to case, therapy should be initiated only upon the occurrence of symptoms. 1. Early initiation of therapy in asymptomatic patients did not result in any improvement of disease-specific survival or overall survival (OS). 31 2. If complete remission and long PFS are to be achieved, Induction therapy utilizing rituximab in combination with chemotherapy [such as CHOP, FC (fludarabine and cyclophosphamide), Bendamustine, etc] should be used. 32 3. Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab remains an alternative in patients with low risk profile or contraindications for a more intensive chemoimmunotherapy. 33,34 4. Induction treatment followed by Rituximab maintenance therapy for 2 years improves PFS (75% vs 58% after 3 years, P <0.0001). 35 In relapsed disease, a repeat biopsy is strongly recommended to rule out a secondary transformation into aggressive lymphoma. In early relapses (<12 months), a non-cross-resistant scheme should be preferred (e.g. Bendamustine after CHOP or vice versa). Other options in the treatment of relapsed disease include high dose chemotherapy with ASCT, Radioimmunotherapy and in a select group of younger patients with a high-risk profile, a potentially curative Allogeneic Haematopoietic Stem cell transplantation (Allo-HSCT). 505

Medicine Update 2012 Vol. 22 Table 3: International Prognostic Index (IPI) for NHL Factor Adverse prognosis Age >60 y Ann Arbor stage III or IV Serum LDH level Above normal No. of extranodal sites of involvement 2 Performance status ECOG PS 2 or equivalent *ECOG PS = Eastern Cooperative Oncology Group Performance Status; LDH = lactate dehydrogenase T-CELL DIFFERNTIATION THYMIC MEDULLA, BLOOD CD8+ Naive T cell CD4+ LYMPH NODE PARACORTEX ANTIGEN CD4+ CD8+ Effector/memory T cell Effector/memory T cell CD8+ CD4+ GERMINAL CENTER Activated T Cell CD4+ TFH t(2;)(p23;)??? t(5;9)(q33;q22) NODAL-BASED PTCLs ALK+ALCL Null>CD4+>CD8+ CD30+ cytotoxic ALK rearrangement STAT3 activation ALK-ALCL Null > CD4+ > CD8+ CD30+ cytotoxic distinct from ALK+ALCL PTCL, NOS: CD4+> CD8+ PDGFRα activation subgroups according to NFKappa B activation, proliferation signature, CD30 expression PTCL with follicular pattern SYK-ITK gene fusion AITL CD4+ CD10+ CXCL13+ TFH signature, prominent microenvironment imprint Fig. 2: Fig. 1 : B-Cell Lymphoma Molecular Pathogenesis (Ref No. 11) Diffuse Large B Cell Lymphoma Young low- and low intermediate-risk patients: 6 to 8 cycles of combination chemotherapy with CHOP regimen combined with six to eight doses of rituximab (R- CHOP) given every 21 days is the current standard for CD20+ diffuse large-cell non-hodgkin s lymphoma of all stages. 36 Consolidation by radiotherapy to initial sites has no clear proven benefit. Young high-intermediate and high risk patients: There is no current standard with sufficient efficacy. 6-8 cycles of chemotherapy with R-CHOP are most frequently applied. Dose-dense (R-CHOP-14; R-CHOP given every 2 weeks) or dose-intensive (like R-ACVBP regimen given every 2 weeks followed by sequential consolidation) regimens could also be administered. 37 The role of radiotherapy in partial remission remains to be established in patients treated with rituximab and evaluated with PET. Patients aged more than 60 years: Eight cycles of R- CHOP given every 21 days is the current standard. 38 Small series have shown that the combination of rituximab with attenuated chemotherapy could induce complete remission and long survival. CNS prophylaxis: Patients with high intermediate- and high-risk IPI, especially those with testicular lymphoma, > 1 extra-nodal site, elevated LDH, etc are at higher risk of CNS relapse. 39,40 CNS prophylaxis is recommended in this population. Relapsed and Refractory DLBCL: In suitable patients with adequate performance status (no major organ dysfunction, age <65 70 years) a salvage regimen with association of rituximab and chemotherapy followed in responsive patients by high-dose treatment with ASCT support is recommended. Salvage regimens such as R- DHAP or R-ICE may be adequate. 41,42 Gene Expression Profiling (GEP) has been used to identify 3 different subtypes of DLBCL: Germinal Centre B-Cell (GCB) subtype, Ativated B-Cell (ABC) subtype and Type 3 which includes PBML (Primary B-Cell Mediastinal Lymphoma) and cases that cannot be classified as either. 43 GEP is not yet recommended for routine clinical use, though Immunostaining algorithms have been developed to differentiate between these subtypes. 44 Burkitt Lymphoma Patients with Burkitt lymphoma or one of its variants are treated commonly with a brief-duration, high-intensity regimen incorporating CNS prophylaxis. 45-47 Selected patients with high-risk features are then candidates for ASCT or Allo-HSCT during their first complete or partial remission. 506

Lymphoma: An Update for Physician 100 Stage II (n = 583) 50 HI L LI (A) 100 Stage III (n = 385) % of Patients 50 H HI L 100 Stage IV (n = 912) (B) 50 L HI LI H (C) Fig. 3: Histopathology of (A) Follicular Lymphoma, (B) Burkitt Lymphoma, and (C) Classic Hodgkin Lymphoma Today, most adult patients with Burkitt lymphoma are cured with appropriate therapy. Future Currently, multiple new and novel agents are being developed for treatment of Lymphomas. Molecular profiling of tumors has allowed the prognosis to be determined more accurately 0 0 2 4 6 8 10 Year Fig. 4 : Survival among 1880 patients in Ann Arbor Stages II, III and IV, according to risk group defined by the IPI. L denotes low risk, LI low intermediate risk, HI high Intermediate risk, and H high risk Ref no. 18 and has potentially identified new targets for treatment. New monoclonal antibodies against a wide range of T-cell and B-cell surface markers are in clinical development. Other strategies, including immunotherapies including immunodrug conjugates, vaccine strategies, antisense oligonucleotides, and novel small molecules like immunomodulatory drugs, histone deacetylase inhibitors, mammalian target of rapamycin (mtor) inhibitors like Everolimus, etc are being developed for treatment of this disease. Future studies will need to be done to determine their role in Lymphomas. 507

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