Lymphoproliferative disorders(CLL,HD,NHL,MM)
Dr. Abdulhak Alnuemi FICMS,CABMLymphadenopathy General considerations
Anatomical Site of the enlarged node (s): cervical,axillary&mediastinal Vs submandibular , Inguinal Size of the enlarged node(s): other clinical characteristic : Texture Mobility Tenderness Reactive hyperplasia: is the most common Histopathological diagnosis of the excised lymph nodes.Lymph nodes features suggestive of diagnosis other than LPD
1. Localized & tender enlarged node - usually draining an area of infection . 2. Stony hard nodes suggest carcinoma . 3. Isolated occipital or posterior auricular lymphadenopathy: consider scalp infection or viral illness . 4. Enlarged & tender Inguinal nodes: suggests lower extremity infection . 5. Bilateral hilar lymphadenopathy (with out mediastinal mass) in a young patient strongly suggestive of Sarcoidosis . 6. Left supraclavicular nodes is likely to point to intra- abdominal cancer rather than Lymphoma.Chronic Lyphocytic Leukemia general consideration & cl/p
Indolent clonal disease of B-lymphocyte chr by accumulation of mature looking but immunoincompetent lymphocytes in blood ,LNs and BM.CLL is disease of elderly , either asymptomatic discovered incidentally or presented with fatigue , lymphadenopathy (80%), splenomegally , hepatomegally (50%)Complications: AIHA , AIT , Richter synd…chang to aggressive B-cell lymphomaChronic Lyphocytic Leukemia
Diagnosis of CLL Peripheral blood: >5.0 x 109 B lymphocytes /L Immunophenotype of CLL cells: CD5+, CD19+, CD20+, CD23+ . Bone marrow lymphocytes ( %) >30Rai staging 0: Bone marrow and blood lymphocytosis only 1: Lymphocytosis with enlarged nodes 2: Lymphocytosis with enlarged spleen and/or liver 3: Lymphocytosis with anaemia 4: Lymphocytosis with thrombocytopenia
CLL stage predicts survival and informs treatment decisions
Binet staging A : Less than three enlarged nodes/nodal groups, Hb > 100 g/L; platelets > 100 x 109/L B : Three or more enlarged nodes/nodal groups Hb > 100 g/L; platelets > 100 x 109/L C : Hb < 100 g/L; platelets < 100 x 109/L regardless of number of lymphoid areas involved ..................................................................................................... # Head & neck , including the Waldeyer ring ( this counts as one area even if more than one group of nodes are enlarged ) Axillae ( involvement of both axillae count as one area) Groins ,including superficial femorals counts as one area.
Rai staging
0: Bone marrow and blood lymphocytosis only 1: Lymphocytosis with enlarged nodes 2: Lymphocytosis with enlarged spleen and/or liver 3: Lymphocytosis with anaemia 4: Lymphocytosis with thrombocytopeniaBinet staging
A: Fewer than three enlarged nodes/nodal groups, Hb > 100 g/L; platelets > 100 x 109/L B: Three or more enlarged nodes/nodal groups Hb > 100 g/L; platelets > 100 x 109/L C: Hb < 100 g/L; platelets < 100 x 109/L regardless of number of lymphoid areas involved
Low risk Intermediate High risk
Watch and wait Begin treatment
Survival (yrs)
14–175–73 CLL stage predicts survival and informs treatment decisions
Patients with intermediate, high-risk, or active disease Active disease defined as any of the following: Progressive marrow failure Massive/progressive/symptomatic splenomegaly Massive nodes or progressive/symptomatic lymphadenopathy Progressive lymphocytosis – lymphocyte doubling time <6 months Refractory autoimmune anaemia and/or thrombocytopenia Weight loss, significant fatigue, fever, night sweats Which patients are eligible for treatment?
Treatment options for previously untreated CLL
Chemotherapy: Alkylating agents (chlorambucil, cyclophosphamide) Nucleoside analogues (Fludarabine,Cladribine, pentostatine)Immunotherapy - monoclonal antibodies: Rituximab -anti CD20 antibody Alemtuzumab-anti CD52 antibodySteroids Fludarabine-based combination…now is the treatment of choice Fludarabine + Rituximab : FR Fludarabine + Cyclophosphamide + Rituximab : FCRCombination chemoChlorambucil & prednisolone - Cyclophosphamide , vincristine , & prednisolone ( CVP) - Cyclophosphamide ,doxorubicine , vincristine , prednisolone (CHOP)SCT BMTHodgkin`s Lymphoma(HL) Lymphomas are heterogeneous group of diseases caused by malignant lymphocytes which usually accumulate in lymph nodes (lymphadenopathy) or infiltrate organs or occasionally spillover into blood (leukemic phase of lymphoma) Lymphomas are devided into Hodgkin disease( HD or HL)& Non- Hodgkin lymphoma (NHL) according to the presence of REED-STERNBERG(RS) cells in HL. Etiology of HL is unknown but in 50% of cases EBV genom has been detected in the lymphoma tissue, its role still unclear.
HL: WHO histological classification The classical classification: (Lymphocyte predominant, Nodular sclerosing, Mixed cellularity, Lymphocyte depleted ) Current classification: 1.Nodular sclerosing 70% usually in young female.. 2.Mixed cellularity 20% ,RS :numerous,usually in old 3. Nodular lymphocyte-predominant 5%,RS cell absent 4. Lymphocyte predomnant 5%, RS cell few usually in men 5.Lymphcyte depleted -rare , with dominance of RS.
Clinical picture of HL HL can present at any age, but it has 2 peaks; first in the second to third decade & the second peak in 50`s. An almost 2:1 male to female ratio. * The Axial lymphatic system is almost always involved whereas distal sites such as Popliteal & Epitrochlear lymph nodes are rarely involved . Most patients presented with Asymmetric, Rubbery , Discrete & Non -tender enlargement of superficial lymph nodes . * Cervical &/or Supraclavicular LN are involved in 60 - 70% of cases . Axillary LN, Inguinal ,Mediastinal.....
* Constitutional symptoms( fever, sweating ,wt loss) ,Pel-Ebestein periodicfever(every2-4wk) is rare. Alcohol induced pain * Clinical splenomegly during the course in 50% of patients .Itching sometimes a prominant symptom. * Liver may be enlarged because of involvement . * Cutanous HL occurs as a late complication in about 10% of patients . Other organs ( BM, GIT , bone, spinal cord or brain) may also be involved * Other rare features as bone pain because of destruction or BM infilteration. osteoblastic lesions similar to that of prostatic cancer . * Back ache because of massive retropritoneal nodes.
* SVC obstruction ( more common in NHL ). * Nephrotic syndrome(heavy proteinuria) is a paraneoplastic but it could be a presenting feature . * Sorethroat & change of voice for long times suggest involvement of Waldeyer`s ring . * Pulmonary symptoms due to pleural effusion (direct pleural involvement or vascular-lymphatic compression ), Airway compression or paranchymal involvement .
Hodgkin's Lymphoma Staging (Ann Arbor ) Sage I one lymph node area Stage II two or more areas confined to one side of Diaphragm Stage III nodes above &below Diaphragm III1 splenic hilar,coeliac,or portal nodes III2 para-aortic,mesenteric or iliac Stage IV extranodal (E ) B-symptoms one or more of Fever, sweating &Weight loss. A----none X Bulky disease (LN>10cm......)
Hodgkin's Lymphoma (investigations)
1. Adequate surgical biopsy reviewed by experienced hematopathologist.CD15 and CD30 positivity 2. Laboratory tests : CBC (anemia normochromic normocytic &eosinophilia high ESR) , serum chemistries (urea creatinin ,uric acid LFTs , protein electrophoresis, urinalysis ,LDH might be high . 3. US, CXR &CT scan of chest include neck , abdomen & pelvis 4. BM aspiration & biopsy (bilateral iliac crest ) unless clinical stage IA or IIA with no anemia or blood count depression. 5. Bone scan, Bone radiographs ,Ga 67 scans for follow- up of residual masses.Treatment of HL Stage 1A &2A ......RADIOTHERAPY 4000 Cgy (rad) ...cure rate up to 90% Stage3&4,also early stages with B- symptom or bulky(>10cm node) disease.....CHEMOTHERAPY ABVD or MOPP (Adriamycin,Bleomycin,Vinblastine&Dacarbazine)
NHL
Predisposing diseases: * Immunodeficiency cong.(as Ataxia telangectasia X-linked combined immunodef. acquired as AIDS * HTLV-1.. Cause adult T-cell leukemia/lymphoma * EBV..endemic type * H.pylori associated MALT
Clinical Picture of Non Hodgkin`s Lymphomas
* Superficial lymphadenopathy ,the majority of patients with asymmetric painless enlargement in one or more peripheral lymph node region . * Constitutional symptoms (fever,sweating& weight loss ) occur less frequently than in HL.Presence of constitutional symptoms is usually associated with disseminated disease , anemia &infections of the type seen in HL may occur .* Liver& spleen are often enlarged &involvement of retroperitoneal or mesenteric nodes is frequent .The GIT is the most commonly involved extranodal site, BM might cause anemia, neutropenia & thrombocytopenia , but cytopenia may also be autoimmune in origin. * Other sites : Waldeyer`s ring (5 - 10%), brain, testis, thyroid & skin (skin is primary in two unusual conditions , closely related to NHL: Mycosis fungoides & Sezary syndrome).
Staging of NHL
Staging of NHL The Ann-Arbor system is used for both HL & NHL, but histopathologic subtype is the prime determinant of survival in NHL.Staging of NHL
Grading of NHL * NHL divided into low, intermediate & high grades that reflect their biologic aggressiveness . * In general small cell size, round or cleaved nuclei, and low mitotic rate characterize low -grade NHL. * The intermediate/ high grade NHL usually manifest larger cell size , prominent nucleoli and a high mitotic rate. * Clinically ,it is useful to consider low grade NHL as being indolent , whereas intermediate& high grade NHL are aggressive diseases ,with short natural history if it is left untreated.Specific Subtypes of NHL`s most common subtypes in sequence are : Follicular Lymphomas Large B-Cell Lymphomas CLL / SLL Multiple Myeloma
LOW GRADE LMPHOMAS Lymphocytic lymphomas Are closely related to CLL &many regard this lymphoma as a tissue phase of CLL.Most patients are elderly with slowly progressive disease .Treatment is a long the lines of CLL. Lympho plasmacytoid lymphomas Are often associated with the production of monoclonal immunoglobulin M (IgM),also termed Waldenstrom`s macroglobulinemia. Complications are anemia & hyperviscosity syndrome.
Follicular lymphoma This is the most common type of NHL`s (45%). Follicular NHL`s according to cellular composition include: follicular small cleaved , mixed , and large cell Follicular small cleaved & mixed lymphomas are generally considered to be low grade lymphomas & large cell type as intermediate grade . Follicular lymphomas are positive for CD10 &CD20 and negative for CD5. usually associated with the t(14,18) which results in up regulation of bcl -2 (bcl-2 is proto- oncogene located on chr 18 ,considered a potent inhibitor of Apoptosis).
Patients are likely to be middle aged or elderly& their disease is often of benign course for many years . The median survival from diagnosis is around 9 years. Presentation is usually with painless lymphadeno- pathy (85%) and the majority of patients will have stage III or IV disease at time of presentation . sudden transformation may occur to aggressive diffuse cell histology (often characterized by P53: tumour suppressor gene mutation ), sometimes associated with leukemic phase transformation.
Marginal zone Lymphomas Are typically extranodal & usually localized .MALT Lymphomas come into this category & it is the most common form ,. Splenic marginal zone B- Lymphoma is usually associated with circulating `Villous` lymphocytes.
MALTomas group of extranodal NHL`s,usually localized (early stages).Stomach is the commonst site ,lung ,breast &other sites can be affected.Gastric MALToma is clearly associated with H. pylori &typically regress after its eradication. Other MALTomas are associated with autoimmune diseases such as Hashimotos thyoiditis & Sjogren`s syndrome .Many of these were designated in the past as Pseudolymphoma
INTERMEDIATE TO HIGH GRADE NHL Mantle cell lymphoma Typical presentation is lymphadenopathy& B-symptoms often there is BM infiltration and tumor cells in blood .There is usually t(11:14) .Response to chemotherapy is poor .
HIGH GRADE LYMPHOMAS Diffuse large cell lymphomas (DLCL) The most common aggressive lymphoma is DLCL (one third of cases).In contrast to most low grade NHL`s ,localized presentation (stage I&II disease) are common . GIT,Waldeyer`s ring & CNS are extranodal sites likely to be affected .Localized presentation is highly curable (80%). Burkitt Lymphoma : Endemic &Sporadic types . B-Cell lymphoblastic lymphoma :this is B-lineage acute lymphoblastic leukemia (ALL) & Treated similarly .
The mentioned previously are B-CELL LYMPHOMAS(80%) T- CELL LYMPHOMAS : (20%) referred to as CUTANEOUS T- CELL LYMPHOMA MYCOSIS FUNGOIDES An indolent low grade lymphoma with pruritic intermittent eczematous features end with plaques . SEZARY SYNDROME is a variant of( CTCL) : Diffuse Erythroderma with circulating malignant T -cells (Sezary cells : more than 10 %) .
Ivestigations of NHL In addition to investigations needed in suspected HD,the following shoud be done: *Routin BM aspiration& trphine biopsy *Immunophenotyping (blood,BM or nodal material) *Plasma protein electrophoresis (paraprotein?) *Uric acid level *HIV testing
Treatment of NHL
Intermediate& high grade lymphomas : R-CHOP (Cyclophosphamide ,Doxurubicine Hydrochloride.Oncovin&Prednisolone) + Rituximab(anti CD20)(R)..Increase response &survival3 cycles for localized disease,6-8 cycles for advanced stages Low grade (Indolent) lymphomas: e.g.. SLL & follicular lymphoma similar to management of CLL Very aggressive lymphomas: e.g. Lymphoblastic lymphoma treatment Similar to ALL with complex cytotoxic regimenRadiotherapy for “pressure symptom” areas, residual disease after CT . RT sometimes used alone for low grade &localized lymphomas (stage one) Autologus SCT for relapsed chemosensetive diseaseCOMPARISON :HL Vs NHL HL NHL size of problem :NHL 8times as frequent as HL B-symptoms 40% 20% Site of involvement nodal extranodal Nodal distribution centripetal(axial) cenrifugal Nodal spread contiguous non conti CNS&BM involv rare More in high grade Cure by CT 80% high grade 60%
Multiple myeloma
Neoplastic proliferation of plasma cells. characterized by plasma cell accumulation in BM and presence of monoclonal protein (paraprotein or M-protein or M-band ),and lytic bony lesions . Normally serum immunoglobulins are polyclonal produced by millions of plasma cells .A monoclonal protein is produced by single plasma cell clone. plasma cells derived from B-cells, normally it constitute less than 4% of nucleated BM cells. In myeloma plasma cells usually 30%. Stimulation of cytokines play an important role IL-6 is potent growth factor for myeloma cells,IL-1 and TNF have osteoclastic activity ,with resultant hypercalcemia and osteolytic bony lesions.Clinical picture of MM
Majority of patients are above 40 year old ,peak in the 7th.decade. Bone pain esp. backache ,path fractures ,vertebral collapse ,occasionally spinal cord compression. Features of anemia Recurrent infections: defective antibody production ,abn. Cell mediated immunity& in advanced disease neutropenia. Feature of hypercalcemia: polyuria, polydipsia, constipation , vomiting ,lethargy.Clinical picture of MM(cont.)
features of renal failure (causes : dehydration , pyelonephritis ,Bence-Johns proteinuria , hypercalcemia, uric acid nephropathy &possibly Amyloidosis) Bleeding tendency (paraprotein interfere with platelet &coagulation factors function, thrombocytopenia in advanced disease. Amyloidosis (macroglosia ,carpal tunnel ,diarrhoea) Hyperviscosity syndrome (purpura, hemorrhages, visual disturbance ,CNS features ,neuropathy &heart failure)Diagnosis of MM(WHO)
Major criteria1.Increased plasma cells in BM more than30%). 2. Quantitative Paraprotein in serum(IgG more than 3.5gm/l, IgA more than 2.5gm/dl or urine BJ proteinuria more than 1gm/24 hrs3. Tissue plasmacytomaMinor criteria1.Plasmacytosis bet 10-30%2.par protein level less than major criteria conc3.Reduced level of normal immunoglobulin to less than 50% of normality.4.Osteolytic lesions …skull ,rarely only generalized osteoporosisDiagnosis :at least one major and one minor.