Pathology > Basic Hematology > White Cell Disorders > Lymphoma: Clinical - Non-Hodgkin

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 blood (leukemic).


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 females (17,000).


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 eitologic mechanism.

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.


Lymphoma: Non-Hodgkin-Clinical-Staging

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:

  1. the age of the patient - certain lymphomas are more common in particular age groups; younger patients tend to have better prognoses than older patients,
  2. the clinical history - especially
    1. a) the nature of the onset of lymphadenopathy (location; sudden vs.gradual) and the nature of associated symptoms
    2. b) occupational history-pneumoconioses-hilar & mediastinal nodes -manual labor-epitrochlear;axillary;inguinal
    3. c) exposure to animals (tularemia;catscratch) and drugs (Dilantin)
  3. 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)
  4. 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



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)
Diagnostic Significance of Anatomic Location
  • 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 node syndrome
  • 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 lymphomas
  • Mediastinal: lymphomas (Hodgkin lymphoma), thymomas, Çastleman's disease
  • 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 yr
B. Follicular, predominantly small cleaved cell------------------ 7.2 yr
C. Follicular, mixed, small cleaved and large cleaved cell--------- 5.1 yr


D. Follicular, predominantly large cell, cleaved and/or non-cleaved-- 3 yr
E. Diffuse, small cleaved cell ----------------------------------3.4 yr
F. Diffuse, mixed, large and small cell --------------------------2.7 yr
G. Diffuse, large cell, cleaved or noncleaved ---------------------1.5 yr


H. Large cell, immunoblastic -(B- or T-cell type)-----------------1.3 yr
I. Lymphoblastic----------------------------------------------2.0 yr
J. Small noncleaved cell (Burkitt's and non-Burkitt's)------------- 0.7 yr

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 Rx.

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 disease-free survivals.

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 regimen.


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 nonspecific dermatitis.

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 appearance.



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 diagnosis.

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 negative.

With the results of this information you determine that this man most likely has:

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.

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