Lecture 9 in hematology by Dr.Alaa F. Alwan
Non-Hodgkin’s lymphomas
Non-Hodgkin’s lymphomas (NHLs) are malignant proliferations of the lymphoid
tissues that can be distinguished from Hodgkin’s lymphoma by a variety of clinical
and histological features. NHLs are a disease of predominantly elderly persons, with a
median age around 50–70 yr, often have an extranodal involvement. About 90% of
the NHLs are derived from a malignant B-cell, the remaining cases from T-cells,
natural killer (NK) cells, or undifferentiated cells.
NHLs are more frequent than Hodgkin’s lymphoma and have an annual incidence of
about 15–20 new cases per 100,000 people.
ETIOLOGY
The etiology of NHLs cannot be determined in most cases. viral or bacterial infections
increases the likelihood of NHLs. HIV, Epstein-Barr virus (EBV) A human retrovirus
(HTLV-1) that is associated with acute T-cell leukemias or lymphomas. Helicobacter
pylori and mucosa-associated lymphoid tissue (MALT)-type gastric lymphomas
Chronic infection with the hepatitis C virus has been associated with the development
of NHL predominantly of the marginal zone type. Infections with Borrelia burgdorferi
the etiological agent of Lyme disease, are associated with some forms of cutaneous
lymphomas.
Cytogenetic and Molecular Markers in Non-Hodgkin’s Lymphomas
Follicular lymphoma t(14;18)
Mantle cell lymphoma t(11;14)
B-cell chronic lymphocytic leukemia Trisomy 12
Burkitt’s lymphoma t(8;14)(q24;q32), c-myc t(2;8)(p12;q24) t(8;22)(q24;q11)
Anaplastic large-cell lymphoma t(2;5) Alk
CLINICAL FEATURES AND DIAGNOSTIC STRATEGIES
Patients with lymphoma present most frequently with lymph node swelling
(lymphadenopathy) that may be either peripheral (e.g., axillary, cervical, inguinal) or
involve central locations (e.g., mediastinal tumor, abdominal lymph nodes).
In most cases, the enlarged lymph nodes are painless, but also other lymphoma
subtypes, may have an extranodal spread: the gastrointestinal tract or solid organs
such as the liver; rarely, the CNS can be involved. In such cases, the clinical
symptoms may be different. For example, the first symptoms of gastric lymphoma
may be dyspepsia or discomfort in the upper abdomen. When the bone marrow is
involved, the patient may present with anemia, leukopenia, or thrombocytopenia.
Similarly to patients with Hodgkin’s lymphoma, patients with NHL may also have
systemic or B-symptoms (fever, night sweats, or weight loss).
The different categories of NHL can be divided into two major groups:
1. Low-grade (indolent) NHL: these lymphomas have an indolent course, do not
always need treatment, but cannot be cured by most present approaches. Examples are
the follicular lymphomas and CLL.
2. High-grade (aggressive) NHL: these lymphomas have an aggressive clinical course
and, if untreated, are rapidly fatal. In a fraction of these NHL, cure is achieved with
chemotherapy. Examples are Burkitt’s lymphomas and diffuse large B-cell
lymphomas (DLBCLs).
Diagnostic Strategies for the Non-Hodgkin’s Lymphomas
1. History and clinical examination Ask for B symptoms and palpate all lymph
nodes, liver, and spleen
2. Laboratory studies Obtain complete laboratory status, including blood counts,
sedimentation rate, white cell differential, clotting tests, lactate
dehydrogenase, B2-microglobulin, total protein, serum electrophoresis,
quantitative immunoglobulins, immunoelectrophoresis if a monoclonal protein
is suspected, creatinine, urea, uric acid, GOT, GPT, alkaline phosphatase;
haptoglobin, Coombs’ test; HIV serology
3. Chest radiograph (in two planes) CT scan of the thorax
4. CT scans of the abdomen Ultrasound of the abdomen and the neck FDG-PET
scan
5. Lymph node biopsy should be excisional or incisional or tru-cut biopsy no role
for fine needle biopsy just in selected cases
6. Bone marrow biopsy Bone marrow aspiration (with immunophenotyping to
detect lymphoma infiltration) (if leukemic presentation, immunophenotyping
can be done from blood)
7. ECG, Echo
DIFFUSE LARGE B-CELL LYMPHOMA
This is the most frequently occurring NHL. It includes lymphomas predominantly
classified in the former Working Formulation as diffuse large-cell, diffuse mixed-cell,
or immunoblastic, and lymphomas classified as diffuse centroblastic, diffuse
centroblastic/centrocytic, and immunoblastic in the Kiel classification.
Histopathologically, a diffuse proliferation of large, transformed lymphoid cells is
found. The nuclei have a vesicular chromatin, prominent nucleoli, basophilic
cytoplasm, and a moderate to high proliferation fraction.
Prognostic Factors in High-Grade NHL
Factors (each contributing one point) that enter into this International Index are age
greater than 60 yr, reduced performance status, clinical stage III or IV, increased
lactate dehydrogenase (LDH), and extranodal manifestation in two or more locations.
Treatment
The treatment of large-cell lymphomas depends on the stage of disease. Patients with
disseminated disease (generally stages III and IV) are given six to eight cycles of
R-CHOP (Rituximab, cyclophosphamide, hydroxydaunomycin, Oncovin®
[vincristine], and prednisone) or a comparable regimen..
FOLLICULAR LYMPHOMA
The combined group of follicular lymphomas or follicle center lymphomas makes up
the second most frequent type of NHL (approx 20–30% of all cases of NHLs). In
many countries, an increased incidence of follicular lymphomas has been observed.
Pathologically, the follicular lymphomas have a characteristic picture that resembles
normal germinal centers. Centrocytes are mixed with centroblasts and form a
neoplastic germinal center. The growth pattern is usually follicular
At the molecular level, about 90% of patients with follicular lymphomas have the
t(14;18) (q32;q21) translocation. Translocation t(14;18) leads to an overexpression of
the bcl-2 protein. The immunophynotype of follicular lymphomas (as determined on
tissue sections or in cell suspensions) is CD19+, CD20+, CD10+ in most cases, CD3-
ve , and CD5-ve.
Clinical Symptoms
The clinical course of follicular lymphomas is indolent in most cases. The median age
of patients with follicular lymphomas is around 50–60 yr. The disease most often
begins with peripheral lymphadenopathy, and the mediastinum is rarely enlarged.
Less than one-fifth of the patients have B-symptoms. The bone marrow is involved in
about half of the patients, typically showing nodular infiltration. The clinical
symptoms are often subtle and caused by the enlarged lymph nodes; para-aortic
lymph nodes or an enlarged spleen may cause abdominal fullness or other local
symptoms. An extranodal manifestation is observed in about 10% of the patients
(gastrointestinal tract, rarely in the skin).
Treatment
1. OBSERVATION (WATCH-AND-WAIT STRATEGY)
indicated for asymptomatic patients with advanced disease (stage III–IV) who do not
have B-symptoms or other complications caused by thelymphoma..
2. RADIOTHERAPY
indicated in stages I and II without bulk (usually as involved or extended-field
radiation with 30–40 Gy).
3. SYSTEMIC CHEMOTHERAPY like R-CHOP
MANTLE CELL LYMPHOMA
The mantle cell lymphomas have a specific cytogenetic marker, the t(11;14)
translocation,
Clinical Symptoms
The major symptom of mantle cell lymphomas is the enlargement of lymph nodes.
About 80% of patients at diagnosis are already at an advanced stage (III or IV). About
30% of patients have B-symptoms. Almost two-thirds of the patients have an enlarged
spleen. The bone marrow is involved in two thirds of the cases, and in some patients a
leukemic dissemination can be found already at diagnosis.
Treatment
The optimal chemotherapy is R-CHOP achieved superior remission rates greater than
90%.