LYMPHOMAS Mousa Qasim Hussein 21th Dec.2015
Neoplasms arise from lymphoid tissue, and are Diagnosed from pathological finding on biopsy As Hodgkin or non-Hodgkin lymphoma. *the majority are of B-cell origin.Hodgkin lymphoma : The histological hallmark is the presence of Reed-Sternberg cells, which are malignant lymphoid cell Of B-cell origin . They are often only present in small numbers but are Surrounded by large numbers of reactive normal T-cells, Plasma cells and eosinophils.
Reed-Sternberg cell. Reed-Sternberg cells are large, abnormal lymphocytes that may contain more than one nucleus. These cells are found in Hodgkin lymphoma.
In the center of the photomicrograph is a classic Reed-Sternberg cell,a binucleate cell with large “owl’s eyes” eosinophilic nucleoli.
Epidemiology : Incidence :approximately 4 new cases/ 100 000 population/ year. Sex ratio :slight male excess (1.5: 1). Age :median age 31 years; first peak at 20-35 year and second at 50-70 years.
Aetiology : -Unknown. -More common in patients from well-educated Background and small families. Three times more likely a past history of infectious - Mononucleosis but no causal link to Epstein-Barr virus Infection proven.
WHO pathological classification and incidence : Type histology incidence Nodular lymphocyte- 5% Predominant Classical HL *nodular sclerosing 70% *Mixed cellularity 20% *Lymphocyte-rich 5% *lymphocyte-depleted Rare
Nodular sclrosis H.L.is the most common subtype and is composed of large tumor nodules showing scattered lacunar classical RS cells set in a background of reactive lymphocytes, eosinophils and plasma cells with varying degrees of collagen fibrosis/sclerosis.
Is a common subtype and is composed of numerous classic RS cells admixed with numerous inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma cells without sclerosis.
Mixed cellularity Hodgkins lymphoma
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Nodular lymphocyte predominance showing characteristic L and H cells(popcorn cells
Lymphocyte rich H.L.Is a rare subtype, show many features which may cause diagnostic confusion with nodular lymphocyte predominant B-cell Non-Hodgkin's Lymphoma (B-NHL). This form also has the most favorable prognosis.
Nodular lymphocyte predominant HL is a slow-growing , localised And rarely fatal. *the nodular sclerosing type accounts for the initial peak in young Patients and is more common in women. *Mixed cellularity is more common in the elderly peak. *lymphocyte rich HL usually present in men. Lymphocyte-depleted HL is rare and probably represents large cells Or anaplastic non-Hodgkin lymphoma.
Clinical features : There is painless rubbery Lymphadenopathy , usually in the neck Or supraclavicular fossa; the lymph nodes may fluctuate in size.
Young patients with nodular sclerosing disease may have large Mediastinal mass which are surprisingly asymptomatic but may cause Dry cough and some breathlessness.
Chest x-ray shows widening of the mediastinum.
CT scan shows Hodgkin's lymphoma surrounding the trachea and narrowing its lumen.Isolated subdiaphragmatic nodes occur in fewer than 10% at diagnosis. Hepatosplenomegaly may be present but does not alwaysindicate disease in those organs. Spread is contiguousfrom one node to the next and extranodal disease, such as bone, brain or skin involvement, is rare.
Clinical stages (ANN ARBOR classification) : *stage I :involvement of a single lymph node region (I) or extralymphatic site (IA E) . *stage II :involvement of two or more lymph node regions( II) or an extralymphatic site and lymph node regions on the same side of (above or below )the diaphragm(II E ). *stage III :involvement of lymph node regions on both sides of Diaphragm with (III E) or without (III ) localised extralymphatic Or involvement of the spleen (III S) or both (III SE) *stage IV diffuse involvement of one or more extralymphatic tissue, e.g. liver or bone marrow. A no systemic symptoms B weight loss, drenching sweats The lymphatic structures are defined as the lymph nodes, Spleen, thymus, Waldeyers ring, appendix and peyers patches
Ann Arbor staging
Stage I Involvement of a single lymph node region or of a single extranodal organ or site(ⅠE)Ann Arbor staging
Stage II: two or more lymph node regions on the same side of the diaphragmlocalized extranodal organ and one or more lymph node regions on the same side of the diaphragm(ⅡE)Ann Arbor staging
Stage III lymph node regions on both sides of the diaphragm or with localized extranodal organ (III E) or spleen (IIIs)or both (III ES).
Ann Arbor staging
Stage IV: Diffused or disseminated involvement of one or more extranodal organs, with or without associated lymph node enlargement. BM,LIVER,CNS, EFFUSIONAnn Arbor staging
Group AWithout general symptoms Group BWith general symptomsunexplained fever , >38C, lasting over 3 daysnight sweating weight loss, >10% of body weight within 6 monthsInvestigations The aim of investigations not only to diagnose lymphoma but also To determine the extent of disease. *full blood count may be completely normal. A normochromic, normorcytic Anaemia may be present and , together with lymphopenia , is a bad Prognostic factor. *ESR may be raised. *Renal function test are required to ensure function is normal prior to Treatment. *Liver function may be abnormal in the absence of disease or reflect Hepatic infiltration. An obstructive pattern may be caused by nodes At the porta hepatis. *LDH measurement , as raised levels are an adverse prognostic factor.
*Chest X-ray may show mediastinal mass. *CT scan of chest and abdomen to permit staging. Bulky Disease (greater than10 cm in a single node mass) is an Adverse prognostic factor. *Lymph node biopsy may be undertaken surgically or by Percutaneous needle biopsy under radiological guidance.
Management : Treatment options include radiotherapy, chemotherapy Or a combinations of the two . Radiotherapy : Indications for radiotherapy : *stage I disease . *stage II A disease with three or fewer areas involved. *after chemotherapy to sites where there was originally bulk disease. *to lesions causing serious pressure problems.
RADIOTHERAPY
Disease above the diaphragm mantle field covering the mediastinum and the supraclavicular and cervical lymph nodes. Disease below the diaphragm inverted- Y field covering the periaortic lymph nodes, the inguinal lymph nodes, and the splenic area.*Careful planning is required to limit the dose delivered To normal tissues. *Fertility is usually preserved after radiotherapy. *women receiving breast irradiation during the treatment Of chest disease have an increased risk of breast cancer. *patients continuing to smoke after lung irradiation are at Particular risk of lung cancer.
HODGKIN’S LYMPHOMA: Treatment Chemotherapy All patients with B symptoms Stage II disease with more than three areas involved Stages III and IV disease Patients should receive at least six cycles of chemotherapy to complete response ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine ChlVPP
. Standard therapy of early-stage patients usually includes additional treatment with radiotherapy to the involved lymph nodes after four courses of ABVD. Treatment response is assessed clinically and by repeat CT and newer scanning modalities such as positron emission tomography (PET).
ABVD chemotherapy can cause cardiac and pulmonary toxicity, due to doxorubicin and bleomycin, respectively. The incidence of infertility and secondary myelodysplasia/AML is low with this regime.
Patients with advanced-stage disease are most commonly managed with chemotherapy alone. Standard treatment in the UK is 6–8 cycles of ABVD, followed by an assessment of response. As with early disease, achieving PET-negative remission predicts a better long-termremission rate. Overall, the long-term disease control/cure rates are lower with advanced disease
Patients with disease which is resistant to therapy may be considered for autologous HSCT
Combined modality therapy :Radiotherapy may be given to the original sites of bulky disease After treatment by chemotherapy to reduce the risk of relapse.This form of treatment carries the greatest risk of long –termComplications.Over 90% of patients with early-stage HL achieve complete remission when treated with chemotherapy followed by involved field radiotherapy, and the great majority are cured. The major challenge is how to reduce treatment intensity, and hence long-term toxicity, without reducing the excellent cure rates in this group.
Prognosis
Between 50 and 70% of those with advanced-stage HL can be cured
Patients who fail to respond to initial chemotherapy have a poor prognosis but some may achieve long-term survival after autologous BMT. Patients relapsing within a year of initial chemotherapy have a good salvage rate with autologous HSCT. Patients relapsing after 1 year may obtain long-term survival with further chemotherapy alone.
The Hasenclever index can be helpful in assigning approximate chances of cure when discussing treatment plans with patients
Non-Hodgkin lymphoma (NHL) Represents a monoclonal proliferation of lymphoid cells And may be of B-cell(70%) or T-cells (30%) origin. NHL are classified as low or high grade on the basis of Their proliferation rate . High grade tumours are dividing rapidly , have only being present for a matter of weeks before diagnosis and may be life-threatening. Low-grade tumours are dividing slowly, may have been present For many months before diagnosis and have an indolent fashion.
Epidemiology Incidence *12 new cases /100 000 people per year. Sex ratio *slight male excess. Age *median age 65-70 years.
Aetiology *no single causative abnormality described . *lymphoma is a late manifestation of HIV Infection. *specific lymphoma types are associated with EBV, human Herpesvirus8(HHV8) and HTLV infection. *the development of gastric lymphoma can be associated With Helicobacter pylori infection. *some lymphomas are associated with specific chromosome Lesions; the t(14:18) translocation in follicular lymphoma Result in the desregulated expression of the BCL-2 gene Product which inhibits apoptotic cell death. *lymphoma occurs in congenital immunodeficiency states And in immunosuppressed patients post organ transplantation.
Of all cases of NHL ,85% are either high-grade diffuse Large cell NHL or low grade follicular NHL. Other forms of NHL , including mantle cell lymphoma And malt lymphomas , are less common.
The current WHO classification stratifies according toCell lineage.Clinically the most important factor is grade, which is A reflection of proliferation rate .HIGH –GRADE NHL has high proliferation rates , rapidly Produces symptoms, is fatal if untreated ,but potentiallyCurable.LOW GRADE NHL has low proliferation rates, may beAsymptomatic for many months before presentation, runAn indolent course, but is not curable by conventionalTherapy.
[FOLLICULAR LYMPHOMA]. Follicular lymphoma is the 2nd most common B-cell non-Hodgkin lymphoma after diffuse large B-cell lymphoma. It comprises up to 20% of lymphoma in adults in the USA and in Western Europe. As the name implies the lymphoma takes a “follicular” or nodular pattern of growth with or without diffuse areas.
Diffuse large B-cell lymphoma
Peripheral T-cell lymphoma
Clinical features : Patients present with lymph node enlargement which may Be associated with systemic upset ; weight loss, sweat, Fever and itching. Hepatosplenomegaly may be present. Extranodal disease is more common in NHL ,with involvement Of bone marrow , gut ,thyroid , lung ,skin, testis, brain and More rarely , bone . Extranodal disease is more common in T-cell disease, whilst Bone morrow involvement is more common in Low-grade (50-60%) than high grade(10%) disease. Compression syndromes may occur; gut obstruction Ascites, superior vena caval obstruction and spinal cord Compression may all be presenting features.Staging The same staging system is used for both HL and NHL but NHL is more likely to be stage III or IV at presentation.
Investigations: These are as for HL but in addition the following should Be performed : *routine bone marrow aspiration and trephine. *Immunophenotyping of surface antigens to distinguish T-and B-cell tumours. this may be done on -blood. -marrow Cytogenetic analysis to detect chromosomal translocations and molecular testing for T cell receptor or immunoglobulin gene rearrangements, if available-Nodal material. .
*Immunoglobulin determination. Some lymphomas are associated with IgG or IgM praroteins serve as as marker for treatment response. *Measurement of uric acid levels. some very aggressive high-Grade NHL are associated with very high urate levels, which can Precipitate renal failure when treatment is started. *HIV testing .this may be appropriate if risk factors are present
Management : Low-grade NHL: *Asymptomatic patients may not require therapy Indications for treatment : *marked systemic symptoms. *lymph node adenopathy causing discomfort or dysfigerment. *bone marrow failure. *compression syndrome.
I-Radiotherapy : Can be used for localised stage I disease. II-Chemotherapy : most patients will respond to oral therapy with chlorambucil Which is well tolerated .more intensive I.V chemotherapy in Younger patients produce better quality of life but no Survival benefit. neither therapy will cure patients. III-Monclonal antibody therapy : Humanised monoclonal antibodies can be used to target Surface antigen on tumour cells, and induce tumour cell Apoptosis directly.
Rituximab :anti-CD20 antibody has been shown to induce Durable clinical response in up to 60%of patients. at present Only recommended as last-line therapy for stage III and IV Follicular lymphoma. synergistic effect are seen when treatment Is combined with standard chemotherapy.
IV-Transplantation. Particular interest centres on the role of high-dose chemotherapy and HSCT in patients with relapsed disease. Such high-dose therapy improves disease-free survival but longer follow-up is awaited before conclusions can be drawn about cure.
High-grade lymphoma Patients with diffuse Large B-cell NHL need treatment at initial presentation. I CHEMOTHERAPY: The majority (more than 90%)will need I.V combination Chemotherapy. The CHOP regimen : C : cyclophosphamide H :doxorubicin O :VINCRISTINE P: Prednisolon This regimen remain the mainstay of therapy.
When combined with CHOP chemotherapy, the biological therapy rituximab (R) increases the complete response rates and improves overall survival. R-CHOP is currently recommended as first-line therapy for those with stage II or greater diffuse large B-cell lymphoma .
II RADIOTHERAPY : A few stage I patients without bulky disease may be Suitable for radiotherapy. It is also indicated for a residual localised site of bulk Disease after chemotherapy , and for spinal cord and Other compression syndromes.
III-Transplantation Autologous stem cell transplantation benefits patients With relapsed chemosensitive disease.
Prognosis Low-grade NHL runs an indolent remitting and relapsing course, with an overall median survival of 10 years. Transformation to a high-grade NHL occurs in 3% per annum and is associated with poor survival. In diffuse large B-cell high-grade NHL treated with R-CHOP, some 75% of patients overall respond initially to therapy and 50% will have disease-free survival at 5 years.
*for high-grade NHL, 5 year survival ranges from 75% in those With low risk scores: 1-age less than 60 2- stage I or II, one or Fewer extranodal sites. 3-normal LDH 4-good performance Status.
Prognosis is further refined according to the international prognostic index (IPI).
1-increasingAge. 2- advanced stage. 3- concomitant disease . 4-araisedLDH ) .
for high-grade NHL, 5 year survival 25%in those With high risk scoresRelapse is associated with a poor response to further chemotherapy (< 10% 5-year survival), but in patients under 65 years, bone marrow transplantation improves survival.