Lymphoma Haematological Neoplasia — Overview n Leukemias

Lymphoma

Haematological Neoplasia - Overview n Leukemias: Acute & Chronic, n Myeloid & Lymphoid n n Lymphomas: n n Hodgkins & Non-Hodgkins Premalignant: Myeloproliverative - MPS n Myelodysplastic - MDS n

Central lymphoreticuular system is thymus & BM It is primary malignant proliferative Tumour arising from the peripheral Lymphoreticular system ( nodal and extra nodal)

Hodgkin lymphoma Thomas Hodgkin (1798 -1866)

Epidemiology of lymphomas n n n 5 th most frequently diagnosed cancer overall for both males and females > females incidence NHL increasing over time n Hodgkin lymphoma stable n less frequent than non-Hodgkin lymphoma n overall M>F = 3 : 1 n peak incidence in 3 rd decade n

Associated (etiological? ) factors n n n EBV infection smaller family size higher socio-economic status caucasian > non-caucasian possible genetic predisposition other: HIV? occupation? herbicides?

Hodgkin lymphoma n n n cell of origin: germinal centre B-cell Reed-Sternberg cells (or RS variants) in the affected tissues most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

B-cell development CLL MCL stem cell memory B-cell mature naive B-cell germinal center B-cell lymphoid precursor progenitor-B LBL, ALL pre-B immature B-cell MZL CLL MM DLBCL, FL, BL, HL plasma cell

A possible model of pathogenesis transforming event(s) EBV? loss of apoptosis cytokines germinal centre B cell RS cell inflammatory response

Lymphoma - Gross

Hodgkins lymphoma

Reed-Sternberg cell

Hodgkins lymphoma cells

Reed-Sternberg cell The Scream, 1893 Edvard Munch

RS cell and variants classic RS cell lacunar cell popcorn cell (mixed cellularity) (nodular sclerosis) (lymphocyte predominance)

Hodgkins Lymphoma: n n Painless, firm lymphadenopathy, Fever* Eosinophilia Only Reed-Sternberg cells malignant (B cell) Classification(WHO): Classic Hodgkins: n n n Lymphocyte predominant. Nodular Sclerosis. Mixed cellularity. Lymphocyte depleted. Nodular lymph. predominant (non-classic)

Hodgkin’s Disease Nodular Sclerosing n < 80% n Supraclavicular & mediastinal n Stage I&II b Lymphocyte Predominant n 5 % n Cervical LN n Stage I &II a

Hodgkin’s Disease Mixed Cellularity n > 20 % n Retroperitoneal n Stage II & III Lymphocyte Depleted n < 5 % n Extra nodal system n Stage III & IV

Hodgkin’s Disease n Presentation n Asymmetric lymphadenopathy— 90% Firm, rubbery n Supraclavicular fossa n n n Spleen, liver (extranodal sites relatively uncommon except in advanced disease Constitutional symptoms— 1/3 of cases n Fever, night sweats, anorexia, weakness, weight loss

Lymphadenopathy in HL n n n n n Number one or two groups Site mostly cervical Size usually small Shape discrete Consistency india rubbery or firm Mobile No skin involvement No tenderness No fixation

Lymphadenopathy in NHL n n n n n Number multiple Site mostly extra nodal Size usually large Shape matted Consistency hard & cystic Fixed skin stretched & red tender fixation

Lymphadenopathy in Lymphoma HL n n n n n Number one or two groups Site mostly cervical Size usually small Shape discrete Consistency india rubbery or firm Mobile No skin involvement No tenderness No fixation NHL n n n n n Number multiple Site mostly extra nodal Size usually large Shape matted Consistency hard & cystic Fixed skin stretched & red tender fixation

Extranodal manifestations (a) SVC compression --dilated Neck veins (b) RLN ---hoarsness of voice (3) Mediastinal (c) Trachea & bronchi--cough& dyspnea (d) Lung--- Dyspnea & effusion (5) Hepatomegally--- Ascites dt • Hepatic dysfunction • Peritoneal invasion (6) jaundice Prehepatic • hemolytic autoimmune • hypersplenism Hepatic– • cholestatic • hepatitis Posthepatic – LN at porta hepatis (1) Cervical lymphadenopathy (2) Hilar LN bronchial compression which cause segmental atelectasis (4) Splenomegally dt infiltration or hyperplasia (7) Stomach & bowel malabsorption syndromes (8) Bone deposites • Sever pain • Pathological fractures (9) Neurological (12) • cord compression Anaemia • Cranial nerve palsy Hypersplenism • Root pains BM infiltration Cytotoxic drugs (11) Mycosis fungoids (10) Skin nodules

The challenge of lymphoma classification Biologically rational classification Clinically useful classification Diseases that have distinct • morphology • immunophenotype • genetic features • clinical features Diseases that have distinct • clinical features • natural history • prognosis • treatment

Staging of lymphoma Stage III Stage IV A: absence of B symptoms B: fever, night sweats, weight loss

Hodgkin Disease

Lymphoma Row of enlarged lymph nodes

Diagnosis:

Hodgkin’s Disease n Evaluation n H&P Biopsy = Reed-Sternberg cells Staging w/u n n Similar to NHL Laparotomy n Controversial From, Principles and Practice of Pediatric Oncology, Lippincott Williams & Wilkins, P 640.

Hodgkin’s Disease n Localized disease n n Extended field XRT Disseminated disease MOPP = nitrogen mustard, vinblastine, procarbazine, prednisone n ABVD = adriamycin bleomycin, vincristine, dacarbazine n

Laboratory Diagnosis: n Haematological: n n Bone marrow: n n n Normocytic normochromic anemia, High ESR* Leucocytosis, Eosinophilia, lymphopenia Leukoerythroblastic picture - BM infiltration* Normal, or late involvement. Trephine biopsy- diffuse or follicular infiltration Biochemical: n n n High serum LDH – poor prognosis Hypercalcemia, Alkaline phosphatase, Uric acid. Serum transaminases & Bilirubin – Liver

Laboratory Diagnosis: n Haematological: n n Bone marrow: n n n Normocytic normochromic anemia, High ESR* Leucocytosis, Eosinophilia, lymphopenia Leukoerythroblastic picture - BM infiltration* Normal, or late involvement. Trephine biopsy- diffuse or follicular infiltration Biochemical: n n n High serum LDH – poor prognosis Hypercalcemia, Alkaline phosphatase, Uric acid. Serum transaminases & Bilirubin – Liver

Laboratory Diagnosis: n Immunological: Monoclonal gammopathy –B cell NHL, Myeloma n Low normal gammaglobulins n Autoimmune hemolytic anemia – auto ab. n n Karyotypic/Genetic: t(14; 18) – B cell follicular (14* heavy chain) n t(11; 14) – diffuse NHL n

Radiological n n n Chest x ray Bone scan Bone x ray if +ve bone scan or bone pains CT scan of chest & abdomen & pelvis Ga 67 scan SPRCT n PET to evaluate residuals n

Mediastinal Lymph nodes-NHL

LN biopsy n Must whole LN as destruction of the architecture is of diagnostic value and n also Reed Sternberg in HL id diagnostic n

Additional work up in NHL n Flow cytometry Peripheral blood n Bone marrow detect haematological involvement n n Diagnostic spinal tab in Lymphoblastic lymphoma n Burkitt’s lymphoma n n Upper GIT& small bowel series & endoscopy in S&S of GIT

Diagnostic laparotomy n Indicated only in HL stage I&IIa ( as supraclavicular enlargment = 40% abdominal involvement) n Technique 1. 2. 3. 4. 5. 6. 7. Systemic LN examination Biopsy from suspicious LN Splenectomy Wedge biopsy from liver Ovariopexy Appendectomy Putting silver clips at the site of involved LN

Hodgkin’s Disease n Localized disease (Stage I & II) n Extended field XRT n n Recently IFRT + new modality chemotherapy ABVD Stage III a n n Above diaphragm ---- Mantle below diaphragm ----Inverted Y Extended field RT IFRT + ABVD Multi agent chemotherapy ABVD or MOPP Disseminated disease (Stage III b & IV ) n n MOPP = nitrogen mustard, vinblastine, procarbazine, prednisone ABVD = adriamycin bleomycin, vincristine, dacarbazine

Radiotherapy

Treatment and Prognosis Stage Treatmen t I, II ABVD x 4 & radiation III, IV ABVD x 6 Failurefree survival 70 -80% Overall 5 year survival 80 -90% 60 -70% 70 -80%

Hodgkin’s Disease n Survival Stages I, II, and III = 90% n Stage IV = 75 -80% n

Long term complications of treatment n infertility MOPP > ABVD; males > females n sperm banking should be discussed n premature menopause n n secondary malignancy n n skin, AML, lung, MDS, NHL, thyroid, breast. . . cardiac disease

Non-Hodgkins Lymphoma (NHL)

Mechanisms of lymphomagenesis n n Genetic alterations Infection Antigen stimulation Immuno-suppression

NHL – Classification: n n n According to cell type n T cell, B cell, Histiocytic & Misc. NHL According to Clinical grade n Low grade, Intermediate & High grade NHL. Histopathological n Diffuse/Follicular NHL, n Small, Intermediate & Large cell NHL Ex: Lennert’s lymphoma is a low grade T cell NHL. Burkitt’s lymphoma, a high grade B cell NHL

Kiel Classification of NHL n B Cell NHL: Low Grade: lymphocytic, plasmacytic, centrocytic, mixed centrocytic centroblastic. n High Grade: Centroblastic, Immunoblastic, Burkitts, lymphoblastic. n n T Cell NHL: Low Grade: lymphocytic, mycosis, Lennerts n High Grade: immunoblastic, lymphoblastic etc. n n Rare types:

NCI – Working Formulation n Low-grade NHL: n n n Intermediate-grade NHL: n n n Follicular large cell Diffuse small cleaved High-grade NHL: n n n Small lymphocytic Follicular small cleaved Immunoblastic Lymphoblastic Miscellaneous: Histiocytic, Mycosis etc.

Non-Hodgkin lymphoma Incidence Diffuse large B-cell lymphoma Follicular lymphoma Other NHL

Follicular lymphoma n n n most common type of “indolent” lymphoma usually widespread at presentation often asymptomatic not curable (some exceptions) associated with BCL-2 gene rearrangement [t(14; 18)] cell of origin: germinal center B-cell

Diffuse large B-cell lymphoma n n n most common type of “aggressive” lymphoma usually symptomatic extranodal involvement is common cell of origin: germinal center B-cell treatment should be offered curable in ~ 40%

NHL- Histologic types Diffuse - & - Follicular

NHL- Histologic types Small – Intermed. – Large

Lymphoma classification n (based on 2001 WHO) B-cell neoplasms n n T-cell & NK-cell neoplasms n n Precursor B-cell neoplasms (2 types) Mature B-cell neoplasms (19) B-cell proliferations of uncertain malignant potential (2) Precursor T-cell neoplasms (3) Mature T-cell and NK-cell neoplasms (14) T-cell proliferation of uncertain malignant potential (1) Hodgkin lymphoma n n Classical Hodgkin lymphomas (4) Nodular lymphocyte predominant Hodgkin lymphoma (1)

Clinical manifestations n Variable severity: asymptomatic to extremely ill n time course: evolution over weeks, months, or years n n Systemic manifestations n n fever, night sweats, weight loss, anorexia, pruritis Local manifestations lymphadenopathy, splenomegaly most common n any tissue potentially can be infiltrated n

Lymphadenopathy in NHL n n n n n Number multiple Site mostly extra nodal Size usually large Shape matted Consistency hard & cystic Fixed skin stretched & red tender fixation

Extranodal manifestations (a) SVC compression --dilated Neck veins (b) RLN ---hoarsness of voice (3) Mediastinal (c) Trachea & bronchi--cough& dyspnea (d) Lung--- Dyspnea & effusion (5) Hepatomegally--- Ascites dt • Hepatic dysfunction • Peritoneal invasion (6) jaundice Prehepatic • hemolytic autoimmune • hypersplenism Hepatic– • cholestatic • hepatitis Posthepatic – LN at porta hepatis (1) Cervical lymphadenopathy (2) Hilar LN bronchial compression which cause segmental atelectasis (4) Splenomegally dt infiltration or hyperplasia (7) Stomach & bowel malabsorption syndromes (8) Bone deposites • Sever pain • Pathological fractures (9) Neurological (12) • cord compression Anaemia • Cranial nerve palsy Hypersplenism • Root pains BM infiltration Cytotoxic drugs (11) Mycosis fungoids (10) Skin nodules

Non Hodgkin

Lymphoma spread to Spleen

Lymphoma Intestine

A practical way to think of lymphoma Category Non. Hodgkin lymphoma Survival of untreated patients Curability To treat or not to treat Generally defer Rx if asymptomat ic Treat Years Generally not curable Aggressive Months Curable in some Very aggressive Hodgkin lymphoma Indolent Weeks Curable in some Treat All types Variable – months to years Curable in most Treat

Staging of Lymphoma

Burkitt’s Lymphoma n n n Unusual, B-Lymphoblastic high grade Young african children, jaw bones Isolated histiocytes, starry sky pattern EBV infection related. t(8; 14) Chemotherapy – good response But relapse usual, 30% cure.

Burkitt’s Lymphoma

Burkitt’s Lymphoma

Burkitt’s Lymphoma L. N.

Non specific LN

Tuberculosis of LN

Metastasis LN