Lymphoproliferative Lymphoproliferative

disorders(CLL,HD,NHL,MM)disorders(CLL,HD,NHL,MM)

Dr. Abdulhak AlnuemiDr. Abdulhak AlnuemiFICMS,CABMFICMS,CABM

LymphadenopathyLymphadenopathy General considerations General considerations

Anatomical SiteSite of the enlarged node (s): cervical,axillary&mediastinal Vs submandibular , Inguinal Size Size of the enlarged node(s):other other clinical characteristic : Texture Mobility Tenderness

Reactive hyperplasiaReactive hyperplasia: is the most common : is the most common Histopathological diagnosis of the excised lymph nodes.Histopathological diagnosis of the excised lymph nodes.

Lymph nodes features suggestive of Lymph nodes features suggestive of diagnosis diagnosis otherother than LPD than LPD

1. Localized & tenderLocalized & tender enlarged node - usually draining an area of infection . 2. Stony hardStony hard nodes suggest carcinoma . 3. Isolated occipitaloccipital or posterior auricularposterior auricular lymphadenopathy: consider scalp infection or viral illness . 4. Enlarged & tender Inguinaltender Inguinal nodes: suggests lower extremity infection . 5. Bilateral hilarBilateral hilar lymphadenopathy (with out mediastinal mass) in a young patienta young patient strongly suggestive of Sarcoidosis . 6. Left supraclavicularLeft 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 lymphoma

Chronic 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 ( %) >30

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 thrombocytopenia

CLL stage predicts survival and informs treatment decisions

Binet stagingA : Less than three enlarged nodes/nodal groups, Hb > 100 g/L;

platelets > 100 x 109/LB : 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 thrombocytopenia

Binet 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 H

igh risk

Watch and w

ait Begin treatm

ent

Survival (yrs)

14–17

5–7

3

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 CLLChemotherapy:

Alkylating agents (chlorambucil, cyclophosphamide)

Nucleoside analogues (Fludarabine,Cladribine, pentostatine)

Immunotherapy - monoclonal antibodies:

Rituximab -anti CD20 antibody

Alemtuzumab-anti CD52 antibody

Steroids

Fludarabine-based combination…now is the treatment of choice

Fludarabine + Rituximab : FR

Fludarabine + Cyclophosphamide + Rituximab : FCR

Combination chemoChlorambucil & prednisolone - Cyclophosphamide , vincristine , & prednisolone ( CVP) - Cyclophosphamide ,doxorubicine , vincristine , prednisolone (CHOP)

SCT BMT

Hodgkin`s Lymphoma(HL)Hodgkin`s Lymphoma(HL)LymphomasLymphomas 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 HLHodgkin disease( HD or HL)&)&

Non- Hodgkin lymphoma (NHL)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 classificationHL: WHO histological classificationThe 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 Clinical picture of HL

HL can present at any ageany age, but it has 2 peaks; first in the second to thirdsecond to third decade & the second peak in 50`s50`s. An almost 2:1 male to female ratio. * The Axial lymphatic systemAxial lymphatic system is almost always involved whereas distal sitesdistal sites such as Popliteal & Epitrochlear lymph nodes are rarely involved . Most patients presented with Asymmetric,Asymmetric, Rubbery , DiscreteRubbery , Discrete & Non -tenderNon -tender enlargement of superficial lymph nodes . * CervicalCervical &/or &/or SupraclavicularSupraclavicular LN are involved in 60 - 70% of cases . Axillary LN, Inguinal ,Mediastinal.....Axillary LN, Inguinal ,Mediastinal.....

* Constitutional symptomsConstitutional symptoms( fever, sweating ,wt

loss) ,Pel-Ebestein periodicfever(every2-4wk) is rare. Alcohol induced painAlcohol induced pain

* Clinical splenomeglysplenomegly during the course in 50% of patients .Itching Itching sometimes a prominant symptom. * Liver Liver may be enlarged because of involvement . * Cutanous Cutanous HL 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 painbone pain because of destruction or BM infilteration. osteoblastic osteoblastic lesions similar to that of prostatic cancer . * Back acheBack ache because of massive retropritoneal nodes.

* SVC obstructionSVC obstruction ( more common in NHL ). * Nephrotic syndromeNephrotic syndrome(heavy proteinuria) (heavy proteinuria) is a paraneoplastic but it could be a presenting feature . * SorethroatSorethroat & change of voicechange of voice for long times suggest involvement of Waldeyer`sWaldeyer`s ring . * Pulmonary symptomsPulmonary symptoms due to pleural effusion (direct pleural involvement or vascular-lymphatic compression ), Airway compression or paranchymal

involvement .

Hodgkin's Lymphoma Staging (Ann ArborHodgkin's Lymphoma Staging (Ann Arbor ) ) Sage II one lymph node area Stage II II two or more areas confined to one side of

Diaphragm Stage III III nodes above &below Diaphragm IIIIII11 splenic hilar,coeliac,or portal nodes IIIIII22 para-aortic,mesenteric or iliac Stage IVIV extranodal (EE ) BB-symptoms one or more of FeverFever, sweatingsweating &WeightWeight lossloss. AA----none XX Bulky disease (LN>10cm......)

Hodgkin's Lymphoma (investigations)Hodgkin's Lymphoma (investigations)

1. Adequate surgical biopsysurgical biopsy reviewed by experienced hematopathologist.CD15 and CD30 positivity 2. Laboratory tests : CBC (anemia normochromic normocytic &eosinophiliaeosinophilia high ESRhigh 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 HLStage 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)

4 2

4 4

4 6

4 8

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NHLPredisposing 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 Clinical Picture of Non Hodgkin`sof Non Hodgkin`s

LymphomasLymphomas

* Superficial lymphadenopathySuperficial lymphadenopathy ,the majority of patients with asymmetricasymmetric painless enlargement in one or more peripheralperipheral lymph node region .

* Constitutional symptomsConstitutional symptoms (fever,sweating& weight loss ) occur less frequently than in HL.Presence of constitutional symptoms is usually associated withassociated with disseminated disseminated disease , anemia &infections of the type seen in HL may occur .

* Liver& spleenLiver& spleen are often enlarged &involvement of retroperitoneal or mesenteric nodes is frequent .The GITGIT is the most commonly involved extranodal site, BMBM might cause anemia, neutropenia & thrombocytopenia , but cytopenia may also be autoimmune in origin.* Other sites : Waldeyer`s ringWaldeyer`s ring (5 - 10%), (5 - 10%), brainbrain, , testistestis, , thyroid thyroid & & skinskin (skin is primary in two unusual conditions , closely related to NHL: Mycosis fungoidesMycosis fungoides & SezarySezary syndrome).

Staging of NHL Staging of NHLStaging 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 NHLGrading 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 NHLlow -grade NHL.

* The intermediate/ high grade NHLintermediate/ 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 indolentindolent , whereas intermediate& high grade NHL are aggressiveaggressive diseases ,with short natural history if it is left untreated.

Specific Subtypes of NHL`sSpecific Subtypes of NHL`smost common subtypes in sequence are :

Follicular Lymphomas Large B-Cell Lymphomas

CLL / SLL Multiple Myeloma

LOW GRADE LMPHOMASLOW GRADE LMPHOMASLymphocytic lymphomasLymphocytic lymphomas

Are closely related to related to CLLCLL &many regard this lymphoma as a tissue phase of CLL.tissue phase of CLL.Most patients are elderly with slowly progressive disease .Treatment is a long the lines of CLL.Lympho plasmacytoid lymphomasmpho plasmacytoid lymphomas

Are often associated with the production of monoclonal immunoglobulin M (IgM),also termed Waldenstrom`sWaldenstrom`s macroglobulinemiamacroglobulinemia. Complications are anemia anemia & hyperviscosityhyperviscosity syndrome.

Follicular lymphomaFollicular lymphomaThis 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 lymphomaslow grade lymphomas & large cell type as intermediate gradeintermediate grade .

Follicular lymphomas are positive for CD10 &CD20 and negative for CD5. usually associated with the t(14,18)t(14,18) which results in upup regulation of bcl -2regulation 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 lymphadenopainless lymphadeno- pathypathy (85%) and the majority of patients will have stagemajority of patients will have stage III or IVIII 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 LymphomasMarginal zone Lymphomas Are typically extranodal & usually localized .MALTMALT Lymphomas come into this category & it is the most common form ,. Splenic marginal zone B- LymphomaSplenic marginal zone B- Lymphoma is usually associated with circulating `Villous` lymphocytes.

MALTomasMALTomasgroup of extranodal NHL`s,usually localized localized (early

stages).StomachStomach is the commonst site ,lung ,breast &other sites can be affected.Gastric MALToma is clearly associated with H. pylori H. pylori &typically regress after its eradication.

Other MALTomas are associated with autoimmuneautoimmunediseases such as Hashimotos thyoiditis & Sjogren`s syndrome .Many of these were designated in the past as PseudolymphomaPseudolymphoma

INTERMEDIATE TO HIGH GRADE NHLINTERMEDIATE TO HIGH GRADE NHL

Mantle cell lymphomaMantle cell lymphoma Typical presentation is lymphadenopathylymphadenopathy& B-

symptomssymptoms often there is BM infiltrationBM infiltration and tumor cells in tumor cells in blood .blood .There is usually t(11:14) .Response to chemotherapy is poor .

HIGH GRADE LYMPHOMASHIGH GRADE LYMPHOMASDiffuse large cell lymphomas (DLCL)Diffuse large cell lymphomas (DLCL)

The most common aggressive lymphomaaggressive lymphoma is DLCL (one third of cases).In contrast to most low grade NHL`s ,localized presentationlocalized 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 LymphomaBurkitt Lymphoma : EndemicEndemic &Sporadic Sporadic types .

B-Cell lymphoblastic lymphomaB-Cell lymphoblastic lymphoma :this is B-lineage acute lymphoblastic leukemia (ALL)(ALL) & Treated similarly .

The mentioned previously are B-CELL LYMPHOMAS(80%)B-CELL LYMPHOMAS(80%)

T- CELL LYMPHOMAS : (20%)T- CELL LYMPHOMAS : (20%)referred to as CUTANEOUS T- CELL LYMPHOMACUTANEOUS T- CELL LYMPHOMA MYCOSIS FUNGOIDESMYCOSIS FUNGOIDESAn indolent low grade lymphoma with pruritic intermittent eczematous features end with plaques .SEZARY SYNDROMESEZARY SYNDROME is a variant of( CTCL) :Diffuse Erythroderma with circulating malignant T -cells (Sezary(Sezary cells : more than 10 %) .cells : more than 10 %) .

Ivestigations of NHL 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 R-CHOP

(Cyclophosphamide ,Doxurubicine Hydrochloride.Oncovin&Prednisolone) + Rituximab(anti CD20)(R)..Increase response &survivalRituximab(anti CD20)(R)..Increase response &survival

3 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 regimen

Radiotherapy for “pressure symptom” areas, residual disease after CT . RT sometimes used alone for low grade &localized lymphomas (stage one)

Autologus SCT for relapsed chemosensetive disease

COMPARISON :HL Vs NHL COMPARISON :HL Vs NHL HL NHLHL NHLsize of problemsize of problem :NHL 8times as frequent as HL :NHL 8times as frequent as HL B-symptomsB-symptoms 40% 20% 40% 20% Site of involvementSite of involvement nodal nodal extranodal extranodal Nodal distributionNodal distribution centripetal(axial) centripetal(axial) cenrifugalcenrifugal Nodal spreadNodal spread contiguous non conti contiguous non conti CNS&BM involvCNS&BM involv rare rare More in high gradeMore in high grade Cure by CTCure by CT 80% high grade 60% 80% high grade 60%

Multiple myeloma• Neoplastic proliferation of plasma cells. characterized by

plasma cell accumulation in BMBM and presence of monoclonal proteinmonoclonal protein (paraprotein or M-protein or M-band ),and lytic bony lesionslytic bony lesions .

• Normally serum immunoglobulins are polyclonal polyclonal produced by millions of plasma cells .A monoclonalmonoclonal protein is produced by single plasma cell cloneclone.

• plasma cells derived from B-cells, normally it constitute less than 4%less than 4% of nucleated BM cells. In myeloma plasma cells usually 30%.usually 30%.

• Stimulation of cytokines play an important role IL-6 IL-6 is potent growth factor for myeloma cells,IL-1IL-1 and TNF TNF have osteoclasticosteoclastic activity ,with resultant hypercalcemia hypercalcemia and osteolyticosteolytic bony lesions.

Clinical picture of MMMajority of patients are above 40 year old ,peak in

the 77thth.decade..decade. • Bone painBone pain esp. backache ,path fractures ,vertebral

collapse ,occasionally spinal cord compression.

• Features of Features of anemiaanemia• Recurrent infectionsinfections: defective antibody

production ,abn. Cell mediated immunity& in advanced disease neutropenia.

• Feature of hypercalcemiahypercalcemia: polyuria, polydipsia, constipation , vomiting ,lethargy.

Clinical picture of MM(cont.)• features of renal failurerenal failure (causes : dehydration ,

pyelonephritis ,Bence-Johns proteinuria , hypercalcemia, uric acid nephropathy &possibly Amyloidosis)

• Bleeding tendencyBleeding tendency (paraprotein interfere with platelet &coagulation factors function, thrombocytopenia in advanced disease.

• AmyloidosisAmyloidosis (macroglosia ,carpal tunnel ,diarrhoea)

• Hyperviscosity syndromeHyperviscosity 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

.

Treatment MM• General: high fluidfluid intake at least 3L daily ,TransfusionTransfusion or

erythropoietinerythropoietin for anemia ,analgesiaanalgesia for bone pain ,treatment of infections ,BisphosphonateBisphosphonate IV. IV.(as Pamidronate, Clodronate or Zolendronic acide) for hypercalcemia &may cause Apoptosis of tumor cells. Allopurinol to prevent urate nephropathy ,DialysisDialysis for renal failue.PlasmapheresisPlasmapheresis for bleeding of hyperviscosity syndrome.

• MPMP , Cyclophosphamide alone , , Cyclophosphamide alone ,VADVAD or or Intensive chemotherapy(as C-VAMP C-VAMP) followed by Autologous SCT.SCT.

• CTDCTD,Cyclophosphamide + Thalidomide+Dexamethasone,Cyclophosphamide + Thalidomide+Dexamethasone• Bortezomib (Velcade) Bortezomib (Velcade) for advanced Myeloma &nowadays 1for advanced Myeloma &nowadays 1stst line line • RADIOTHERAPYRADIOTHERAPY for spinal cord compression by Plasmacytoma

, sever bone pain & pathological fractures..