Lymphoma: Clinical - Non-Hodgkin
Here we will discuss the clinical presentation,staging, treatment
and prognosis different for non-Hodgkin lymphomas.
Non-Hodgkin lymphomas are not only morphologically distinct from Hodgkin
lymphoma, but are clinically distinct as well.
Most non-Hodgkin lymphomas are multicentric or diffuse in their
growth pattern, without evidence of contiguous spread.
n contrast to Hodgkin lymphoma, non-Hodgkin lymphoma usually disseminates
early in the course of the disease and may involve the peripheral
The clinical presentation of non-Hodgkin lymphoma is highly variable,
depending on the initial location and extent of the disease.
People with non-Hodgkin lymphoma classically present with peripheral
lymphadenopathy or enlarged lymph nodes.
Occurrence as a primary extranodal lymphoma is common, representing 10-15%
of all non-Hodgkin lymphoma.
Abdominal, pharyngeal, gastrointestinal, skin, and bone involvement are
frequent early clinical and pathologic findings of non-Hodgkin lymphoma
compared to Hodgkin lymphoma.
Most non-Hodgkin lymphoma patients are asymptomatic, and although weight
loss is a frequent finding, fever, night sweats and pruritus are uncommon.
A leukemic phase occurs in at least10-15% of patients at some point in
the course of the disease. Autoimmune hemolytic anemia (Coombs' positive),
and hypogammaglobulinemia are associated with non-Hodgkin lymphoma more
frequently than with Hodgkin lymphoma.
Non-Hodgkin lymphoma accounted for an estimated 35,600 cases
(83%) of the 43,000 new cases of lymphoma in the United States in 1990.
The incidence of non-Hodgkin lymphoma increases steadily with age and
has been increasing worldwide in the last decade.
Non-Hodgkin lymphoma is slightly more frequent in males (18,600) than
Lymphoma: Non-Hodgkin -Clinical-Etiology
The etiologic causes of non-Hodgkin lymphoma are usually
not specifically identified. Viruses, chronic antigenic stimulation, and
immunosuppression have been implicated in several types of lymphoma.
Immunosuppression related to transplantation (renal, cardiac, T-depleted
bone marrow) is a minor cause of lymphoma, but illustrates a possible
Immunosuppressed individuals often develop a proliferation
of lymphocytes. These are almost always B cells and consist of
multiple distinct clones (some k and others l) - an oligoclonal
population. In some cases, after a period of time, one of the
clones becomes dominant. Usually at this point, the pathologist
sees a malignant lymphoma by histology, often a large cell immunoblastic
or the high grade lymphoma, Burkitt's small noncleaved ML.
What has happened?
What has happened?
First, the T cell immune surveillance system is suppressed or destroyed
either by drugs (given to prevent rejection of the transplant) or by a
virus (ie. HIV).
Second, the B cell population may be antigenically stimulated to proliferate
( ie. EBV; chronic antigenic stimulation).
Third, a chromosomal abnormality occurs, in many cases probably involving
the c-myc oncogene from chromosome 8. Typical might be the t(8;14) which
places the c-myc gene adjacent to the gene for the Ig heavy chain. The
presence of c-myc in the IgH locus appears to bring c-myc under the control
of the promoter region of the IgH gene, resulting in production of the
c-myc product- a DNA binding protein, and uncontrolled growth of B lymphocytes.
The autoimmune diseases (Hasimoto's thyroiditis, rheumatoid arthritis,
systemic lupus erythematosis, Sjogren's syndrome, & celiac disease),
the hereditary immune deficiency diseases (X-linked immunodeficiency,
Wiskott-Aldrich syndrome, ataxia telangiectasia, Bloom's syndrome), and
the acquired immundeficiency disease HIV probably set in motion a similar
series of events.
Epstein-Barr virus (EBV) is closely associated with Burkitt's lymphoma
and HTLV-1 with ATL/L (Adult T cell Leukemia/Lymphoma). HTLV-5 has been
linked to mycosis fungoidies.
Non-Hodgkin lymphomas are staged using the Ann Arbor Classification as
was shown for Hodgkin lymphoma.
Greater than 50% of patients with non-Hodgkin lymphoma present with stage
IV disease and approximately 20% in stage III disease.
Given that over 75% of all cases of non-Hodgkin lymphoma present with
advanced disease and that radiation therapy is insufficient as a cure
for both low grade and high grade lymphoma (widespread disease makes delivery
of sufficient "curative" radiation impossible in most cases), staging
is of lesser importance than with Hodgkin lymphoma.
Staging procedures should involve a thorough history and physical examination,
peripheral blood and bone marrow examination, and CAT scan.
The key diagnostic features are:
- the age of the patient - certain lymphomas are more common in particular
age groups; younger patients tend to have better prognoses than older
- the clinical history - especially
- a) the nature of the onset of lymphadenopathy (location; sudden
vs.gradual) and the nature of associated symptoms
- b) occupational history-pneumoconioses-hilar & mediastinal
nodes -manual labor-epitrochlear;axillary;inguinal
- c) exposure to animals (tularemia;catscratch) and drugs (Dilantin)
- physical examination with special attention to the location and extent
of lymphadenopathy; potential hepatosplenomegaly or abdominal masses,
and to skin lesions (more on next card)
- laboratory tests (CBC;peripheral smear;serologic tests; cobalamin/folate,
cultures; BM biopsy,etc) that assist in establishing the Dx -possibly
avoiding lymph node biopsy or aspiration
Diagnostic Significance of Anatomic Location
- Non-neoplastic: enlarged, flat, and relatively soft
- Neoplastic: enlarged, irregular, and rubbery hard
- Infectious: enlarged, with a variable degree of hardness (possibly
tender, fluctuant,red, warm, and painful)
- Occipital: (rarely neoplastic) inflammatory scalp disorders
- Posterior auricular: rubella, inflammatory scalp disorders
- Anterior auricular: inflammatory disorders of eyelids and conjunctivae
(ocularglandular syndrome), carcinoma
- Posterior cervical: toxoplasmosis, subacute necrotizing lymphadenitis,
trypanosomiasis, inflammatory scalp disorders, head and neck carcinomas
- Anterior cervical : (deep and superficial) oral cavity and upper respiratory
infections, head and neck carcinomas, lymphomas, mucocutaneous lymph
- Submental and submaxillary: infections and neoplasms of the lip and
oral cavity, lymphomas, sinus histiocytosis with massive lymphadenopathy
- Supraclavicular and scalene: (often malignant) intrathoracic and intra-abdominal
carcinomas, lymphomas, sarcoidosis
- Axillary: inflammatory disorders of the upper extremities (e.g., the
ulceroglandular syndromes), lymphomas, carcinomas
- Epitrochlear: inflammatory disorders of the upper extremities non-Hodgkin
- Mediastinal: lymphomas (Hodgkin lymphoma), thymomas, Çastleman's
- Hilar: sarcoidosis (bilateral), carcinomas, lymphomas, pneumoconioses,
tuberculosis, fungal infections
- Retroperitoneal (usually malignant): lymphomas, carcinomas, sarcomas
- Mesenteric: non-Hodgkin lymphomas, carcinomas, nonspecific
- Inguinal and femoral: inflammatory disorders of the lower extremities,
venereal diseases, lymphomas, melanomas, carcinomas
Lymphoma: Non-Hodgkin -Clinical-Therapy
Treatment is largely dependent on the histologic grade of the lymphoma.
The "New Working Formulation" divides lymphomas into three categories
- low grade with indolent behavior; intermediate with unfavorable behavior,
and high grade with aggressive behavior.
"New Working Formulation for Clinical Use"
- A. Small lymphocytic (lymphocytic; plasmacytoid)
- B. Follicular, predominantly small cleaved cell
- C. Follicular, mixed, small cleaved and large cleaved cell
- D. Follicular, predominantly large cell, cleaved and/or non-cleaved
- E. Diffuse, small cleaved cell
- F. Diffuse, mixed, large and small cell
- G. Diffuse, large cell, cleaved or noncleaved
- H. Large cell, immunoblastic -(B- or T-cell type)
- I. Lymphoblastic
- J. Small noncleaved cell (Burkitt's and non-Burkitt's)
In regard to therapy it is paradoxical that low grade lymphoma is rarely
cured by chemotherapy, but that high grade lymphoma is "cured" (long term
disease free survival) by chemotherapy.
Thus, low grade lymphoma is treated palliatively (mild Rx) while high
grade lymphoma is treated aggressively with high dose chemotherapy.
Aggressive chemotherapy refers to high drug doses allowing for greater
killing of tumor cells and penetration of sanctuary sites (CNS, testis)
as well as giving the tumor "no quarter" by using nonmyelosuppressive
Rx (prednisone) at intervals to give the bone marrow a chance to recover
while "keeping the heat" on the lymphoma.
Radiation has a limited role in the treatment of lymphoma. Its primary
role is as adjuvant therapy to chemotherapy. Radiation can be used for
management of low grade, local stage I or early (nonbulky) stage II disease
in some circumstances.
Lymphoma: Non-Hodgkin-Clinical Aspects
"New Working Formulation for Clinical Use" with median survival times
- A. Small lymphocytic (lymphocytic; plasmacytoid)---------------5.8
- B. Follicular, predominantly small cleaved cell------------------
- C. Follicular, mixed, small cleaved and large cleaved cell---------
- D. Follicular, predominantly large cell, cleaved and/or non-cleaved--
- E. Diffuse, small cleaved cell ----------------------------------3.4
- F. Diffuse, mixed, large and small cell --------------------------2.7
- G. Diffuse, large cell, cleaved or noncleaved ---------------------1.5
- H. Large cell, immunoblastic -(B- or T-cell type)-----------------1.3
- I. Lymphoblastic----------------------------------------------2.0
- J. Small noncleaved cell (Burkitt's and non-Burkitt's)-------------
The Low-Grade MLs have 5 year survival rates of 50-70%; Intermediate-Grade
MLs: 35-45%, and
Low grade lymphoma, for example ML,small cleaved cell, follicular
(click button below), is sensitive to chemotherapy, but has a high
recurrence rate despite the therapy.
The other low grade lymphomas (ML,small lymphocytic (click
button below) and ML, follicular mixed) behave similarly.
Observation of asymptomatic patients, the 'watch and wait" approach,
with low grade lymphoma is appropriate, although as already noted radiation
may be used for local stage I disease or as treatment for obstruction
(eg. lymphoma obstructing the bronchus). Low grade lymphoma can convert
to a high grade lesion.
Despite the success of aggressive Rx for intermediate and high grade
lesions, the low grade lesions have not been "cured" by aggressive Rx.
Often symptom free, median survivals of 7-9 yrs are achieved with mimimal
Although indolent, low grade lymphomas are eventually fatal.
The intermediate grade malignant lymphomas:
D. Follicular, predominantly large cell, cleaved and/or non-cleaved
E. Diffuse, small cleaved cell
F. Diffuse, mixed, large and small cell
G. Diffuse, large cell, cleaved or noncleaved
H. Large cell, immunoblastic -(B- or T-cell type)
have median survival times ranging from 3.4-1.3 years with 32-45% survival
at 5 years. Thus intermediate lymphomas fall between the low and high
grade lesions in length of survival.
It is clear that large cell immunoblastic and diffuse large cell lymphomas
(click button below) are similar in behavior and although ML,large
cell immunoblastic is technically placed in the high grade category, its
clinical behavior suppports placement of ML,large cell immunoblastic in
the intermediate grade.
The optimal therapy for follicular,predominately large cell is unknown.
Diffuse mixed ML is generally treated as a large cell ML.
Diffuse SCC (click button below) includes several different
immunologically distinct subtypes.
The intermediate lymphomas, including large cell and large cell immunoblastic
are generally treated with aggressive chemotherapy regimens such as CHOP
or BACOP which have proven records of complete responses and long-term
The survival curve of "favorable" histology shows continuing mortality
with no plateau. The curve of "unfavorable" histology shows early treatment
failures due to resistant disease, but "cure" of a portion as evidenced
by the plateau.
"True" high grade malignant lymphoma includes the lymphoblastic
(ML,Lb) and small noncleaved cell lymphomas. Both have rapidly
progressive clinical courses and a tendency to involve the central nervous
system. For this reason, CNS prophylaxis is a critical part of any treatment
Median survival is 2.0 yrs for ML,Lb and 0.7 yrs for ML,SNC (Burkitt's).
The 5 year survival is approximately 25% for both.
Lymphoma: Non-Hodgkin in Children
Non-Hodgkin lymphoma in children differs from lymphoma in adults.
Lymphoma in children is generally rapidly proliferative, frequently leukemic,
primarily extranodal, but rarely follicular, while the opposite is true
of adult lymphoma.
Most childhood lymphomas are: lymphoblastic (40%), small noncleaved (30%),
and large cell (20%).
The lymphoblastic lymphomas are usually mediastinal and T cell in origin.
The SNC lymphomas tend to be "central" (eg. abdominal) in the US, but
peripheral (eg. jaw) in Africa.
Children develop more pronounced reactions to antigenic stimuli than
do adults, resulting in florid displays of lymphoid hyperplasia in children.
For instance, viral infections such as EBV may generate an impressive
immunoblastic proliferation as a response that can be confused with large
cell immunoblastic ML.
Lymphoma: Non-Hodgkin-Clinical Aspects
Certain of the non-Hodgkin lymphomas have unique clinical and pathologic
features deserving of a closer look. These include:
Mycosis fungoidies (MF) and Sezary syndrome are closely related
and may be considered the disease in skin (MF) and peripheral blood (Sezary).
MF, the most common of the skin lymphomas, characteristically presents
as a patchy dermatitis, evolving into a plaque, and then tumor stage often
accompanied by severe generalized erythroderma. In many cases the diagnosis
is extremely difficult and the patient may have a multi-year history of
The proliferating cells are T helper cells (positive for the pan T antigens
CD 2,3,5,&7 and for the T helper antigen CD4). The etiology is unknown,
although there have been reports of associations with retroviruses.
MF is slowly progressive. There is eventual spread to other organs -
lymph nodes, spleen, liver, etc. The prefered treatment is electron beam
(beta rays) radiation, although various forms of chemotherapy may be employed.
Sezary syndrome is a similar chronic disease with the primary
manifestation in the peripheral blood. The T helper cells lack CD7. The
skin is involved - infiltrating the upper dermis, but not the epidermis
as in MF.
Peripheral Tcell lymphoma represents about 10-15% of non-Hodgkin
lymphomas. Peripheral or differentiated T cell lymphoma is often classified
in the NWF as either diffuse large cell or diffuse mixed.
Closely related terms are Lennert's lymphoma, angiocentric T cell lymphoma,
and angioimmunoblastic lymphadenopathy (AILD). While not always malignant
AILD commonly progresses to an AILD-like T cell lymphoma.
Peripheral T cell MLs are widely diverse in their morphologic appearance
and clinical behavior. Hypercalcemia and hepatocellular dysfunction are
common clinical findings. Recently, a group of peripheral T cell lymphomas
involving ulceration of the skin has been described that are so subtle,
they are often not recognized until late in the patient's course.
Monocyoid B-cell lymphoma is a diffuse B cell lymphoma of the
low grade category. The proliferating B cells have moderate-abundant clear
or pale cytoplasm and small "mature" appearing nuclei. They closely resemble
hairy cell leukemic cells both in morphology and immunology. Monocytoid
B cell are CD19+; CD5-; CD11c+, and usually IgM+. They are CD25-, whereas
hairy cells are CD25+.
Monocytoid B cells may be seen filling the sinuses of some reactive lymph
nodes, ie. toxoplasmosis.
Centrocytic lymphoma is an intermediate grade lymphoma, originally
defined by Lennert in the Kiel classification. At first thought to derive
from small cleaved cells in the germinal center, immunologic data suggests
an origin from mantle zone CD5+ B lymphocytes producing IgM and /or IgD.
In true cases of centrocytic lymphoma there is a t(11;14) resulting in
expression of the bcl-1 oncogene.
In the NWF centrocytic lymphoma would be placed in the category of diffuse
small cleaved cell ML. It is sometimes referred to as intermediately differentiated
lymphocytic lymphoma and as mantle zone lymphoma.
The pattern of growth is usually diffuse, often with a vaguely follicular
Large cell anaplastic lymphoma is seen in all age groups. It appears
that the form seen in young patients and involving the skin has a favorable
prognosis. This form of lymphoma is easily confused with carcinoma.
Large cell anaplastic lymphoma is sometimes referred to as "Ki-1" lymphoma
after the antibody Ki-1 (CD30) which is found in the large cell lymphoma
population. Immunophenotyping is necessary to confirm or establish the
Aggressive chemotherapy is the treatment of choice. Large cell anaplastic
lymphoma arising de novo appears to respond better than large cell anaplastic
that evolves from a previous non-Hodgkin lymphoma.
Extranodal lymphomas represent 10-15% of all non-Hodgkin lymphoma. The
most common extranodal site for lymphoma is the gastrointestinal tract
(stomach-28%; sm intestine-8%; lg intestine-7%).
The majority of "Western" gastrointestinal lymphomas are classified as
diffuse large cell ML and nearly all are of B cell origin. As many as
25% of GI lymphomas are classified as small lymphocytic ML.
The lymphomas usually infiltrate the full thickness of the GI wall forming
large bulky intramural masses. Small noncleaved (Burkitt's) lymphoma often
presents as an ileocecal or mesenteric mass in children.
Be aware of a special type of GI lymphoma - Mediterranean lymphoma (as
distinct from Western lymphoma), in which the lymphoma is either large
cell, large cell immunoblastic, or small lymphocytic ML with plasmacytiod
features. This lymphoma commonly arises in the duodenum or proximal jejunum
and is associated with malabsorptive syndromes. It is also related to
a chain disease (See Plasma Cell Disorders). Note that not all patients
in the Mediterranean region get Mediterranean lymphoma.
True malignant histiocytosis is a rare disorder of monocytic/
histiocytic cells identified by cytochemical and immunologic studies [nonspecific
esterase (NSE); lysozyme; Mac3; Mac387; CD68; a-1-antichymotrypsin].
These must be carefully distinguished from T cell malignancies by both
immunologic and genotypic studies.
Clinically malignant histiocytosis presents as a fulminant and disseminated
disease involving the spleen, liver, bone marrow, and lymph node sinuses.
Early and aggressive chemotherapy is the only hope for this disease which
is rapidly progressive.
In summary, great progress has been made in the treatment
of non-Hodgkin lymphoma in the last 25 years. The careful classification
of lymphomas by morphologic, immunologic, and phenotypic study, and the
development of new chemotheraputic agents and bone marrow transplant techniques
have contributed to this progress.
Despite our advancing knowledge and theraputic abilities non-Hodgkin
malignant lymphoma remains the fifth leading cause of death in the US
even though lymphoma represents only about 5% of all malignancies.
A fifty-five year old man comes to you complaining of vague abdominal
pain that he first noticed about 4-6 weeks ago. Lately he has been losing
weight - 11 lbs. in the last month.
A chest X-ray is normal, but a GI series shows a partial obstruction
of the stomach. No other lymphadenopathy is noted. His peripheral blood
and bone marrow are negative for lymphoma.
With the results of this information you determine that this young man
most likely has:
- A. stage IV, lymphoblastic lymphoma
- B. stage IV, small lymphocytic lymphoma
- C. stage II, follicular small cleaved cell lymphoma
- D. stage I, large cell lymphoma
- E. stage IV, follicular small cleaved cell lymphoma
A sixty-three year old woman comes to you complaining of an almost immediate
sensation of fullness when beginning to eat-early satiety. She has lost
weight -12 lbs over the last year as a result. Lately she has also noted
a "wornout, tired feeling".
Examination of her peripheral blood and bone marrow both show evidence
of involvement by the lymphoma. The WBCc is 17.0 x10 /L.
With this information you determine that this woman most likely has:
- A. ML, small lymphocytic
- B. ML, follicular,SCC
- C. ML, lymphoblastic
- D. ML, follicular, mixed SCC
- E. HD, lymphocyte predominant type
A forty-five year old man comes to you complaining of an erythematous
maculopapular skin rash on his arms, thighs, and abdomen. Physical exam
reveals no evidence of heptosplenomegaly. No mediastinal mass is noted
by CAT scan. The bone marrow aspirate showed occassional atypical lymphocytes.
The peripheral blood showed numerous atypical lymphocytes with convoluted,
highly irregular deep nuclear folding. Immunostaining shows these cells
to be T cells (CD2+; CD3+; CD5+, but CD7 neg) and of the T helper subset
(CD4+), but negative for the IL-2 receptor(CD25). The patient is HTLV-1
With the results of this information you determine that this man most
- A. ML, lymphoblastic
- B. Sezary syndrome
- C. ML, large cell immunoblastic
- D. Mycosis fungoidies
- E. Adult T cell leukemia/lymphoma
What is more characteristic of Hodgkin lymphoma than of non-Hodgkin lymphoma?
- A. leukemic phase
- B. nasopharnygeal involvement at onset
- C. younger age peak
- D. extranodal involvement
Typical features of small noncleaved cell (Burkitt's) lymphoma include:
- A. endemic in central Africa
- B. strongly linked to HTLV-1
- C. a low grade lymphoma
- D. most often a T cell lymphoma
- E. rarely has a leukemic phase
You see a 12-year-old boy from the Shenandoah Valley because of vague
weakness, fever, and abdominal pain. During your physical examination
you find a tender left axillary lymph node.
What is the LEAST likely diagnosis?
- A. ML, lymphoblastic
- B. catscratch disease
- C. ML, small lymphocytic
- D. Infectios mononucleosis
- E. Hodgkin lymphoma
You have reached the end of the Lymphoma section. The right button will
takes you to the Plasma Cell Disorder section.