LYMPHOMA

Hailemariam K(MD)
Introduction
 Malignancies are clinically the most important disorders
of white cells.
 They can be divided into three broad categories based
on the origin of the tumor cells:
A. Lymphoid neoplasms: include a diverse group of
tumors of B-cell, T-cell, and NK-cell origin; like,
 Non-Hodgkin lymphomas (NHLs),
 Hodgkin lymphomas,
 Lymphocytic leukemias, and
 Plasma cell dyscrasias and related disorders.
Cont…
B. Myeloid neoplasms
 Arise from stem cells that normally give rise to the formed elements of the
blood: granulocytes, red cells, and platelets.
 The myeloid neoplasms fall into three fairly distinct subcategories:
 Acute myelogenous leukemias, in which immature progenitor cells
accumulate in the bone marrow;
 Chronic myeloproliferative disorders, in which inappropriately increased
production of formed blood elements leads to elevated blood cell counts; and
 Myelodysplastic syndromes, which are characteristically associated with
ineffective hematopoiesis and cytopenias
C. Histiocytic neoplasms
 represent proliferative lesions of histiocytes.
 Of special interest is a spectrum of proliferations comprising Langerhans
cells (the Langerhans cell histiocytoses).
Cont…
 Two groups of lymphomas are recognized:
 Hodgkin lymphoma and
 Non-Hodgkin lymphomas
 Although both arise most commonly in lymphoid tissues,
 the morphologic appearance, biologic behavior and
clinical treatment of Hodgkin lymphoma are different from
those of most NHLs, making the distinction of practical
importance.
Lymphomas
• Lymphomas - solid tumors of the immune system
 are malignant transformations of normal lymphoid cells
which reside predominantly in lymphoid tissues
• They are divided into two major types:
• Non-Hodgkin’s lymphoma (NHL)
• Hodgkin’s Lymphoma(HL)
 Cont…
• They share a number of important clinical features:
 Commonly present as a solitary or generalized painless
lymphadenopathy.
 Share more or less similar staging systems
 But clinically and biologically distinct
Epidemiology
• Bimodal age distribution
• First peak between 2nd - 3rd decade of life
• Second peak between 5th - 6th decade of life

• Male: Female 2:1 in kids, adults almost equal M:F

• Mixed cellularity (MC) Hodgkin’s Disease is more
common at younger ages
• More common in immune deficiency patients
• In developing countries, more common in young children.
• Median age of 132 Ethiopians with HL was 29 years with
male to female ratio of 2:1
Etiology
• Cause unknown
• Family clustering has been observed –genetic linkage??
• Infectious agents (EBV, HIV etc ) , environmental ,
occupational hazards and a genetically determined
response may play role in the causation and pathogenesis
Clinical presentation
• Non-tender lymph node enlargement (localized)
• neck and supraclavicular area
• mediastinal adenopathy
• other (abdominal, extranodal disease)
• Systemic symptoms (B symptoms)
• fever
• night sweats
• unexplained weight loss (10% per 6 months)
• Other symptoms
• fatigue, weakness, pruritus
• cough , chest pain, shortness of breath, vena cava syndrome
• abdominal pain, bowel disturbances, ascites
• bone pain
Diagnosis of HL
• Is based on microscopic examination of lymph node or
other involved tissue( FNAC, Biopsy)
 It requires identification of diagnostic Reed-Sternberg
cells.
Staging evaluation of HL
• Essential
• Pathologic documentation by hemopathologist
• Physical examination
• Documentation of B symptoms
• Laboratory evaluation
• complete blood count, ESR
• liver function tests
• renal function tests
• lactate dehydrogenase
• Chest radiograph
• Ultrasonography
• CT scan of chest, abdomen and pelvis
• Bone marrow aspiration / biopsy (bilateral)
Cont…
• Essential under certain circumstances
• liver biopsy
• gallium scan
• technetium bone scan
• bone radiographs
• MRI
• bipedal lymphangiogram
• staging laparotomy
• Useful but not essential tests
• cell-surface marker phenotypic analysis
• gene rearrangement analysis
Cont…
Prognostic factors of HL
• Stage is the single most important prognostic factor.
• At any stage, B symptoms confer a poor prognosis
• Age >45yrs, anemia, elevated ESR, BM involvement,
bulky disease and performance status are all difficult to
prove as an independent prognostic importance.
Treatment of HL
 With appropriate treatment about 90% of patients with
Hodgkin disease are curable
• I A,B: radiation therapy
• II A : combination chemotherapy + radiotherapy
• IIB, IIIA,B, IVA,B : combination chemotherapy (+/-
radiotherapy)
Cont…
The most popular chemotherapy regimens used in
Hodgkin's disease include
 ABVD – (doxorubicin, bleomycin, vinblastine, and
dacarbazine) and
 MOPP – (mechlorethamine, vincristine, procarbazine,
and prednisone), or
 Combinations of the drugs in these two regimens.
Today, most patients in the United States receive ABVD,
but a weekly chemotherapy regimen administered for 12
weeks called Stanford V is becoming increasingly popular
Rx Outcome
 Patients who relapse after primary therapy of Hodgkin's
disease can frequently still be cured.
 Patients who relapse after initial treatment with only
radiotherapy have an excellent outcome when treated
with chemotherapy.
 Patients who relapse after an effective chemotherapy
regimen are usually not curable with subsequent
chemotherapy administered at standard doses.
 However, patients with a long initial remission can be an
exception to this rule.
 Autologous bone marrow transplantation can cure half of
patients who fail effective chemotherapy regimens.
Complications of Therapy
• Long term effects of treatment should be taken into
consideration:
- Treatment-related secondary neoplasms
(i.e. AML, NHL and breast cancer)
- Infertility
- Growth consideration
- Long-term organ dysfunction (i.e., thyroid, heart, lung)
Non Hodgkin’s lymphoma
• Encompasses a large number of distinct lymphoid
malignancies that can be recognized on the basis of their
clinical behavior , morphologic appearance ,
immunophenotypic and genetic markers.
• Range from indolent to aggressive lymphomas
• An 8x as frequent as Hodgkin’s lymphoma
• Increasing in incidence and mortality
Epidemiology
• Can occur at any age
• Overall incidence, and incidence of subtypes, varies with
location:
• Burkitt’s lymphoma- in tropical Africa
• Small intestinal lymphoma- in Middle East
• Adult T cell leukemia-lymphoma in Japan and Caribbean
Cont…
• SLL common in the elderly.
• Lymphoblastic lymphoma usually affects male
adolescents and young adults.
• Burkit lymphoma occurs in children and young adults.
• Follicular lymphoma occurs mainly in middle-adult life.
• Patients with HIV/AIDS develop aggressive, high grade
lymphomas.
Etiology of NHL
• Immune suppression
• Congenital (Wiskott-Aldrich)
• Organ transplant (cyclosporine)
• AIDS
• Increasing age
• DNA repair defects
• Ataxia telangiectasia
• Xeroderma pigmentosum
Cont…
• Chronic inflammation and antigenic stimulation
• Helicobacter pylori inflammation - stomach
• Chlamydia psittaci inflammation - ocular adnexal tissues
• Autoimmune disorders
• EBV and Burkitt’s lymphoma
• HTLV-I and T cell leukemia - lymphoma
• HTLV-V and cutaneous T cell lymphoma
• Hepatitis C
Natural History of NHL
• Doubling time varies between days (Burkitt’s lymphoma)
to years(low grade lymphoma).
• Early BM involvement & hematogeneous and non-
contigeous dissemination characterizes NHL.
• Extra-axial nodes including epitrochlear & mesentric
nodes are often involved.
• Progression of NHL from low grade to intermediate or
high grade occurs in 20 to 30% of the cases
Working Classification of NHL
• Low Grade
• Small Lymphocytic
• Follicular small-cleaved cell
• Follicular mixed small-cleaved and large cell
• Intermediate Grade
• Follicular large cell
• Diffuse small cleaved cell
• Diffuse mixed small and large cell
• Diffuse large cell
• High Grade
• Large cell immunoblastic
• Lymphoblastic
• Small non-cleaved cell (Burkitt's and non-Burkitt's type)
Clinical Features
• Spreads in a centrifugal fashion, skipping anatomic
regions.
• Peripheral lymphadenopathy –most common presentation
especially in those with indolent lymphoma.
• The LAP may be waxing & waning in character initially.
• Most indolent lymphomas also have BM involvement
Cont…
• Aggressive lymphomas present with large mediastinal or
abdominal masses.
• Burkitt’s lymphoma in Africans presents with massive
head & neck tumors that involves the facial and jaw
bones.
• Lymphoblastic lymphoma of T-cell origin often presents
with a huge mediastinal mass and CNS or BM
involvement .
• Constitutional (B) symptoms are relatively rare in NHL at
presentation.
Staging of NHL
• The Ann Arbor staging system is used for the clinical
staging .
• But histologic subtype is the prime determinant of survival
in NHL
Survival
• Low grade lymphomas:- are rarely curable and median
survival is 4 to 6 years.
• Intermediate/high grade lymphoma:- survival curves
generally display two components in treated patients-a
rapid fall in the 1st 1 or 2 years followed by eventual
plateau, 80 to 90% of patients with stage 1 or early stage
2 and 30 to 40% with stage 3 or 4 may be curable.
Treatment of NHL
• Indolent lymphomas
• A 10-15% in Stage I or II
• Potentially curable
• Local radiotherapy
• An 85-90% Stage III or IV
• Incurable
• Treatment does not prolong survival
Reasons to Treat in Advanced Indolent Lymphomas

• Constitutional symptoms
• Anatomic obstruction
• Organ dysfunction
• Cosmetic considerations
• Painful lymph nodes
• Cytopenias
Treatment Options in Advanced Indolent Lymphomas

• Observation only.
• Radiotherapy to site of problem.
• Systemic chemotherapy
• Oral agents: Chlorambucil and prednisone
• IV agents: CHOP(Cyclophosphamide, Doxorubicin, Vincristine, and
Prednisone), COP (Cyclophosphamide, Vincristine, and
Prednisone), fludarabine, 2-CDA.
• Antibody against CD20: Rituximab, Bexxar, Zevalin.
• Stem cell or bone marrow transplant
Treatment Options for Early Stage Aggressive Lymphomas

• Often in Stage I or II
• potentially curable
• disseminates through bloodstream early
• must use systemic chemotherapy
• CHOP x 6 cycles
• CHOP x 3 cycles followed by radiotherapy
Treatment Options for Advanced Stage Aggressive Lymphomas

• Systemic chemotherapy
• CHOP (± Rituximab for over 70 age group)
• ± Intrathecal chemotherapy
• Patients with HIV/AIDS and CNS involvement
• ± Radiotherapy
• Spinal cord compression, bulky disease
Diffuse Large B-Cell Lymphoma (DLBCL)
• This diagnostic category includes several forms of NHL
that share certain features, including ;
 A B-cell phenotype,
A diffuse growth pattern, and
An aggressive clinical history.
 As a group, this is the most important type of lymphoma
in adults, as it accounts for approximately 50% of adult
NHL.
Clinical Features
 Although the median age at presentation is about 60 years,
 DLBCL can arise at any age;
 they constitute about 15% of childhood lymphomas.
 Patients typically present with a rapidly enlarging, often
symptomatic mass at one or several sites.
 Extranodal presentations are common.
 Although the GIT and the brain are among the more frequent
extranodal sites, these tumors can arise in virtually any organ
or tissue.
 Unlike the more indolent lymphomas (e.g., follicular
lymphoma), involvement of the liver, spleen, and bone marrow
is not common at the time of diagnosis.
 Aggressive tumors that are rapidly fatal if untreated.
Diagnosis of DLBCL
 The diagnosis of diffuse large B-cell lymphoma can be
made accurately by an expert hematopathologist
 Morphologically, the nuclei of the neoplastic B cells are
large (at least three to four times the size of resting
lymphocytes) and can take a variety of forms
TREATMENT DLBCL

 The initial treatment of all patients with DLBCL should be with a

combination chemotherapy regimen.
 The most popular regimen in the is CHOP plus rituximab,
 Patients with stage I or nonbulky stage II disease can be
effectively treated with three to four cycles of combination
chemotherapy with or without subsequent involved-field
radiotherapy.
 The need for radiation therapy is unclear.
 Cure rates of 70–80% in stage II disease and 85–90% in stage I
disease can be expected
Cont…
 For patients with bulky stage II, stage III, or stage IV
disease, six to eight cycles of CHOP plus rituximab are
usually administered.
 A frequent approach would be to administer four cycles
of therapy and then reevaluate.
 If the patient has achieved a complete remission after
four cycles, two more cycles of treatment might be given
and then therapy discontinued.
 Using this approach, 70–80% of patients can be
expected to achieve a complete remission, and 50–70%
of complete responders will be cured.
Burkitt’s Lymphoma
• Burkittʾs lymphoma is endemic in some parts of Africa and
sporadic in other areas, including the United States.
• Histologically, the African and nonendemic diseases are
identical, although there are clinical and virologic
differences
• African variety: jaw tumor, strongly linked to Epstein-Barr
Virus infection.
• In U.S., about 50% EBV infection
Clinical Features
 Both the endemic and nonendemic forms affect mainly children
and young adults.
 Accounts for approximately 30% of childhood NHLs in the United
States.
 In both forms, the disease usually arises at extranodal sites.
 In African patients, involvement of the maxilla or mandible is the
common mode of presentation,
o whereas abdominal tumors involving the bowel, retroperitoneum,
and ovaries are more common in North America.
 Leukemic presentations are uncommon, especially in the
endemic form, but do occur and must be distinguished from ALL.
 Is a high-grade tumor that is among the fastest growing human
neoplasms; however, with very aggressive chemotherapy
regimens, the majority of patients can be cured.
TREATMENT Of Burkitt’s Lymphoma
• Treatment of Burkitt’s lymphoma in both children and adults should
begin within 48 h of diagnosis and
 involves the use of intensive combination chemotherapy regimens
incorporating high doses of cyclophosphamide.
• Prophylactic therapy to the CNS is mandatory.
• Burkitt’s lymphoma was one of the first cancers shown to be curable
by chemotherapy.
• Today, cure can be expected in 70–80% of both children and young
adults when effective therapy is administered precisely.
• Salvage therapy has been generally ineffective in patients in whom
the initial treatment fails, emphasizing the importance of the initial
treatment approach
Adult T-Cell Lymphoma
• Adult T-cell lymphoma is one manifestation of infection by
the HTLV-1 retrovirus.
• Patients can be infected through transplacental
transmission, mother’s milk, blood transfusion, and by
sexual transmission of the virus.
• Patients who acquire the virus from their mother through
breast milk are most likely to develop lymphoma, but the
risk is still only 2.5% and the latency averages 55 years
Cont…
Adult T-cell lymphoma is characterized by;
 Skin lesions,
 Generalized lymphadenopathy,
 Hepatosplenomegaly,
Hypercalcemia, and
 Variable numbers of malignant CD4+ lymphocytes in the
peripheral blood.
The leukemic cells express high levels of CD25, the IL-2 receptor
α chain.
 In most cases this is an extremely aggressive disease, with a
median survival time of about 8 months.
 In 15% to 20% of patients the course of the disease is chronic;
their disease is clinically indistinguishable from cutaneous T-cell
lymphoma
Cont…
• Although treatment with combination chemotherapy
regimens can result in objective responses,
 true complete remissions are unusual, and the median
survival of patients is ~7 months.
• A small phase II study reported a high response rate with
interferon plus zidovudine and arsenic trioxide.
MALT Lymphoma
• Mucosa-Associated Lymphoid Tissue
• Chronic infection of the stomach by Helicobacter pylori.
• MALT lymphoma may occur in the stomach, orbit,
intestine, lung, thyroid, salivary gland, skin, soft tissues,
bladder, kidney, and CNS.
• It may present as a new mass, be found on routine
imaging studies, or be associated with local symptoms
such as upper abdominal discomfort in gastric lymphoma.
• Most MALT lymphomas are gastric in origin.
Cont…
• Most patients with MALT lymphoma have a good
prognosis, with a 5-year survival of ~75%.
• In patients with a low IPI score, the 5-year survival is
~90%, whereas it drops to ~40% in patients with a high
IPI score.
TREATMENT OF MALT Lymphoma
• MALT lymphoma is often localized.
• Patients with gastric MALT lymphomas who are infected with H. pylori
can achieve remission in the 80% of cases with eradication of the
infection.
 These remissions can be durable, but molecular evidence of
persisting neoplasia is not infrequent.
 After H. pylori eradication, symptoms generally improve quickly, but
molecular evidence of persistent disease may be present for 12–18
months.
• Additional therapy is not indicated unless progressive disease is
documented.
• Patients with more extensive disease or progressive disease are
most often treated with single-agent chemotherapy such as
chlorambucil.
• Combination regimens that include rituximab are also highly effective