The malignant lymphomas include Hodgkin’s disease and non-Hodgkin’s lymphomas; both are derived from lymphoid tissue, predominantly from lymph nodes. Lymph nodes are composed of two parts, germinal centers and lymphoreticular tissue. The germinal centers contain lymphoblasts and reticulum cells; these produce the mature lymphocytes and reticulum cells that form the remainder of the lymphoid tissue. Therefore, three main cell types exist in lymph nodes (and other lymphoid tissue): reticulum cells, lymphoblasts, and lymphocytes. Malignancy may arise from any of these three cell types.

Histologic classification of the non-Hodgkin’s lymphomas (NHL)

Rappaport’s classification. In Rappaport’s classification, the non-Hodgkin’s lymphomas are divided into three types based on whatever cell of origin is suggested by the microscopic appearance: lymphocytic lymphoma, histiocytic lymphoma (originally called reticulum cell sarcoma), and undifferentiated. Lymphocytic lymphoma (originally called lymphosarcoma) may, in turn, be subdivided into well-differentiated and poorly differentiated (lymphoblastic) types, depending on the predominant degree of differentiation of the lymphoid cells (Table 7-3). Besides the degree of differentiation, malignant lymphomas may exist in two architectural patterns, nodular and diffuse. In the nodular type, the lymphomatous tissue is distributed in focal aggregates or nodules. In the diffuse type, the lymphomatous cells diffusely and completely replace the entire lymph node or the nonlymphoid area invaded. However, a significant number of cases have both nodular and diffuse components; there does not appear to be a consensus as to what percentage of the tumor must be nodular in order to designate the tumor as nodular. Hodgkin’s disease, which is discussed later, also exists in a somewhat nodular and diffuse form, although the nodular variety is rare. In the malignant lymphomas as a group, the diffuse pattern is more frequent than the nodular one.

Histologic classification of non-Hodgkin's malignant lymphomas (Rappaport modified)

Table 7-3 Histologic classification of non-Hodgkin’s malignant lymphomas (Rappaport modified)

The histiocytic lymphoma category basically includes large cell lymphomas of both lymphocytic and histiocytic origin that may have different nuclear types; but the various possible subclassifications all have roughly the same prognosis. Untreated histiocytic lymphoma has a prognosis comparable with that of acute leukemia. The same is true for the poorly differentiated lymphocytic lymphomas.

The nodular pattern comprises about 40% of NHL. Nodular lymphomas are derived from B-lymphocytes. The nodules in most cases are either predominately small cell, predominately large cell, or mixed large and small cell. The cells contain a chromosomal 14-18 translocation associated with the bcl oncogene. Nodular lymphoma originally was called Brill-Symmers disease, or giant follicular lymphoma, and was originally thought to have a better prognosis than the corresponding diffuse pattern. However, evidence exists that prognosis depends to a considerable extent on the cell type as well as the architectural pattern. This would suggest that the poorly differentiated or more primitive cell types do not have a good prognosis even when they appear in a nodular (“follicular”) form.

It is interesting that 20%-30% of non-Hodgkin’s lymphomas of the nodular or the better differentiated type are reported to eventually undergo change to a diffuse pattern or a less favorable nuclear type.

Rappaport’s classification has been criticized by various investigators. Some wish to include more subclassifications, whereas others believe that the terminology does not reflect cell origin correctly. The majority of cases that would be classified as histiocytic by Rappaport’s criteria have been shown by immunologic or genetic techniques to be of lymphoid origin rather than histiocytic. Nevertheless, Rappaport’s classification still is frequently used in the United States and seems to provide a fairly reliable index of prognosis.

Immunologic characterization of malignant lymphomas

Most classifications of hematopoietic malignancies are based on cell morphology and tissue pattern (often including interpretation of cell origin or even cell function as estimated from morphology). Work that characterizes malignancies involving lymphocytes according to phylogenetic origin of the cells (referred to previously in the section on acute leukemia) has been presented. Lymphocytes have two origins: thymus-derived (T) cells, which functionally are responsible for delayed hypersensitivity cell-mediated immune reactions; and bone marrow-derived (B) cells, which are involved with immune reactions characterized by Ig (antibody) production. T-cells in lymph nodes are located in the deep layers of the cortex and in a thin zone surrounding the germinal centers. B-cells are located in germinal centers and in the outer cortex of lymph nodes; they are precursors of plasma cells. In general, most work to date indicates that multiple myeloma, 98% of CLL, Burkitt’s lymphoma, and approximately 75% of lymphocytic lymphomas (especially the better-differentiated varieties) are of B-cell origin. In childhood ALL about 20% of cases are T-cell, about 2% are B-cell, and 75% are pre-pre-B-cell or Pre-B-cell and do not react in E rosette or surface Ig tests. The T-cell subgroup of childhood ALL has many clinical features in common with a subgroup of the non-Hodgkin’s lymphomas (the lymphoblastic lymphoma of Rappaport’s classification or the convoluted lymphocytic lymphoma of the Lukes-Collins classification; the same neoplasm was referred to in the older literature as Sternberg’s sarcoma). These features include presence of a mediastinal tumor mass, onset in later childhood or adolescence, predominance in males, and poor prognosis. Other T-cell malignancies include mycosis fungoides and the Sйzary syndrome, both sometimes referred to as “cutaneous lymphomas.”

Lukes-Collins classification

Lukes and Collins have published a classification of non-Hodgkin’s lymphomas based on results of immunologic testing of lymphomas, the morphologic appearance of the cell nucleus plus cell size, and their concept of lymphoid cell maturation (see box below). This classification has proved attractive to many institutions because it places those lymphomas of Rappaport’s “histiocytic” category that are actually lymphocytic rather than histiocytic into the lymphocytic lymphoma category and emphasizes cell appearance rather than prediction of cell type. The major problem with the Lukes-Collins classification is that it is frequently difficult to decide whether to assign cells with large noncleaved nuclei to the category of large noncleaved follicular center cells or to the category of immunoblastic sarcoma.

Lukes-Collins Classification of Non-Hodgkin’s Lymphomas (Modified 1982)
I. U-cell (undefined cell) type
II. T-cell types
1. Small lymphocytic
2. Cerebriform lymphocytic
3. Convoluted lymphocyte
4. Immunoblastic sarcoma of T cells
5. Lymphoepithelioid lymphocytic
III. B-cell types
1. Small lymphocyte (CLL)
2. Plasmacytoid lymphocyte
3. Follicular center cell (FCC) types (follicular or diffuse, with or without sclerosis)
a. Small cleaved
b. Large cleaved
c. Small noncleaved
Burkitt’s variant
Non-Burkitt’s variant
d. Large noncleaved
4. Immunoblastic sarcoma of B cells
IV. Histiocytic type
V. Unclassifiable

National Cancer Institute lymphoma panel Working Formulation

In 1980, a panel of well-known authorities on histopathology of malignant lymphomas, collectively known as the National Cancer Institute (NCI) Non-Hodgkin’s Lymphoma Pathologic Classification Project, met in Palo Alto, California, and by 1982 developed a new classification of non-Hodgkin’s lymphoma (see box below), which they called the “Working Formulation.” This classification combines some features of Rappaport’s classification (nodular and diffuse patterns, mixed cell pattern) with the basic nuclear morphologic descriptive terms of Lukes and Collins, plus subdivision by degrees of malignancy as found in the British and Kiel (German) classifications. Although the NCI Working Formulation has somewhat improved pathologist agreement in lymphoma classification, even recognized experts in lymphoma pathology do not unanimously agree in about 15% of cases.

Classification of Non-Hodgkin’s Lymphomas: Non-Hodgkin’s Lymphoma Pathologic Classification Project (“Working Formulation”)
Low grade

Small (noncleaved) lymphocytic

a.Consistent with CLL

Follicular* lymphoma, predominantly small cleaved cell
Follicular lymphoma, mixed small cleaved and large cell

Intermediate grade

Follicular lymphoma, predominantly large cell
Diffuse small cleaved cell
Diffuse mixed small and large cell
Diffuse large cell (cleaved/noncleaved)

High grade

Diffuse large cell of immunoblastic type
Lymphoblastic (convoluted/nonconvoluted)
Small noncleaved cell (Burkitt’s/non-Burkitt’s)


Composite lymphoma
Mycosis fungoides

Chromosome studies in lymphoma

A considerable number of lymphoma patients have chromosome abnormalities. Some lymphoma subgroups have a particular abnormality that occurs more often than all others. Currently, no chromosome abnormality has made a major contribution to diagnosis. Perhaps the closest is the translocation often seen in nodular B-cell lymphoma. For additional information.

Burkitt’s lymphoma

Burkitt’s lymphoma is a B-cell variant of malignant lymphoma that was originally reported in African children. It is now known to occur in children elsewhere in the world. In African Burkitt’s lymphoma, about 50%-70% of affected persons have involvement of the jaw, a site rarely affected by other lymphomas. In non-African Burkitt’s lymphoma, the jaw area is involved in only 12%-18% of patients, a tumor mass is frequently located in the abdomen, single peripheral lymph node groups are involved in about 30% of patients, and widespread peripheral lymphadenopathy is rare. Histologically, the cell nuclei are rather uniform in appearance, and sheets of these cells characteristically include scattered single cells exhibiting phagocytosis (“starry sky appearance”). Appearance of individual Burkitt’s cells resembles that of the FAB acute leukemia B-cell category, and occasional Burkitt’s lymphoma patients in the United States have developed ALL. In addition, occasional patients in the United States have been young adults rather than children. There is a strong association with Epstein-Barr virus infection in African Burkitt’s but much less evidence of Epstein-Barr in American Burkitt’s lymphoma.

Other lymphoma subgroups

A number of subgroups have been described that are not part of current standard classification systems. One example is non-Hodgkin’s lymphoma derived from “mucosa-associated lymphoid tissue” (MALT) areas; originally bronchial mucosa and stomach, but later including some lymphomas of other areas such as salivary gland, thyroid, skin, breast, and thymus. These are mostly B-cell tumors thought to be derived from parafollicular (follicular marginal zone) lymphocytes in the outer portions of the lymphoid mantle zone surrounding germinal centers. These cells include small or medium-sized cleaved lymphocytes and plasmacytoid lymphocytes. The lymphoid aggregates tend to infiltrate into epithelial structures; often remain localized for a considerable time; and when spread occurs it tends to involve other mucosal areas. Another subgroup is known as Mediterranean lymphoma (also called alpha heavy chain disease or immunoproliferative small intestine disease), which is a primary small intestine non-Hodgkin’s lymphoma most common in the Middle East and to somewhat lesser extent in other countries bordering the Mediterranean Sea. These tumors also produce chronic disease and are composed predominantly of plasma cells and plasmacytoid lymphocytes. A third example is the Ki-1 large cell non-Hodgkin’s lymphoma diagnosed with antibody against the CD-30 Ki-1 antigen (originally found in Hodgkin’s disease Reed-Sternberg cells). This is an anaplastic large-cell lymphoma most often (but not always) T-cell that tends to affect younger individuals and is found mostly in lymph nodes, the GI tract, and skin. In lymph nodes it tends to involve the sinuses more than the lymphoid parenchyma and often does not affect the entire lymph node. Prognosis ranges from moderate survival length to short survival.

Hodgkin’s disease

Hodgkin’s disease is usually considered a subgroup of the malignant lymphomas. The basic neoplastic cell is the malignant reticulum cell. Some of these malignant reticulum cells take on a binucleated or multinucleated form with distinctive large nucleoli and are called Reed-Sternberg (R-S) cells. These are the diagnostic cells of Hodgkin’s disease.
Other types of cells may accompany the R-S cells. Therefore, Hodgkin’s disease is usually subdivided according to the cell types present (Fig. 7-2). Besides R-S cells there may be various combinations of lymphocytes, histiocytes, eosinophils, neutrophils, plasma cells, and reticulum cells. The main histologic forms of Hodgkin’s disease are shown in Fig. 7-2, using a classification developed by the U.S. Armed Forces Institute of Pathology (AFIP).

Various histologic classifications of Hodgkin's disease

Fig. 7-2 Various histologic classifications of Hodgkin’s disease.

The most widely accepted pathologic classification today is the one developed by Lukes and co-workers at the Rye Conference in 1965(see Fig. 7-2). This classification combines certain histologic tissue patterns having similar prognosis, resulting in four groups instead of six. Of the groups, lymphocytic predominance comprises about 12% (range, 5%-17%) of patients with Hodgkin’s disease, nodular sclerosing about 45% (27%-73%), mixed cellularity about 30% (16%-37%), and lymphocytic depletion about 10% (3%-23%). Prognosis is relatively good for untreated lymphocytic predominance (9-15 years’ average survival after onset). Lymphocytic depletion behaves like histiocytic lymphoma or acute leukemia, with an average survival of 1 year or less. Mixed cellularity has an intermediate prognosis (average, 2-4 years’ survival). The nodular sclerosing category as a group has a prognosis between that of lymphocytic predominance and mixed cellularity with much individual variation; a considerable number of patients achieve the survival time of patients with lymphocytic predominance Hodgkin’s disease. Life expectancy in Hodgkin’s disease is quite variable, even without treatment, and some patients live for many years with the lymphocytic predominance, nodular sclerosing, and even the mixed cellularity forms.

Also of great importance, especially for therapy, is the degree of spread when the patient is first seen (Table 7-4). Localized Hodgson’s disease has an encouraging possibility of cure by adequate radiotherapy. There is considerable correlation between the tissue histologic patterns and the clinical stage (degree of localization) of disease when first seen.

Clinical findings in malignant lymphoma

Clinically, malignant lymphoma is more common in males. The peak incidence for Hodgkin’s disease is age 20-40, and age 40-60 for other malignant lymphomas. Lymph node enlargement is found in the great majority of cases but may not become manifest until later. Fever is present at some time in at least one half of patients. Staging laparotomy has shown that splenic Hodgkin’s disease occurs in 35%-40% of cases; if this occurs, paraaortic nodes are usually involved. Liver metastasis is found in 5%-10% of cases; if the liver is involved, the spleen is always invaded. In non-Hodgkin’s lymphoma, laparotomy discloses splenic involvement in 30%-40% and hepatic metastasis in 10%-20% of cases, with rather wide variation according to histologic classification. Splenomegaly is not reliable as a criterion for presence of splenic tumor. Bone marrow metastasis is present at the time of diagnosis in 10%-60% of cases of non-Hodgkin’s lymphoma and 5%-30% of cases of Hodgkin’s disease. Lymphocytic lymphoma has a greater tendency to reach bone marrow, liver, or spleen than histiocytic lymphoma, and the nodular form is more likely to metastasize to these organs than the diffuse type.

Laboratory findings in malignant lymphoma

Anemia is found in 33%-50% of cases and is most common in Hodgkin’s disease and least common in histiocytic lymphoma. Occasionally, this anemia becomes overtly hemolytic. The platelet count is usually normal unless the bone marrow is extensively infiltrated. The WBC count is usually normal in non-Hodgkin’s lymphoma until late in the disease; in Hodgkin’s disease, it is more often mildly increased but may be normal or decreased. WBC differential counts are usually normal in malignant lymphoma unless malignant cells disseminate into the peripheral blood or, more commonly, if some other condition is superimposed, such as infection. In Hodgkin’s disease, eosinophilia may occur; in late stages, leukopenia and lymphopenia may be present. Bone marrow needle biopsy in both Hodgkin’s and non-Hodgkin’s lymphoma demonstrates bone marrow involvement more frequently than clot sections or smears. A second biopsy increases the yield by 10%-20%.

Diagnosis of malignant lymphoma

Diagnosis of the malignant lymphomas is established by tissue biopsy, usually lymph node biopsy. The particular node selected is important. The inguinal nodes should be avoided, if possible, because they often contain changes due to chronic inflammation that tend to obscure the tissue pattern of a lymphoma. If several nodes are enlarged, the largest one should be selected; when it is excised, the entire node should be taken out intact. This helps to preserve the architectural pattern and permits better evaluation of possible invasion outside the node capsule, one of the histologic criteria for malignancy.

In difficult cases it is possible (as discussed earlier) to employ immunologic stains on tissue slides or flow cytometry methods to demonstrate B-cell or T-cell lineage; a monoclonal lymphocyte phenotype would be evidence for malignancy. It is also possible to employ nucleic acid probes for Ig rearrangement (B-cells) or TCR rearrangement (T-cells). Some medical centers routinely obtain this information and also attempt to determine the stage of maturation of the cell type for therapeutic and prognostic information.

Differential diagnosis of malignant lymphoma

Several diseases enter into the differential diagnosis of malignant lymphoma. Tuberculosis, sarcoidosis, and infectious mononucleosis all produce fever, lymphadenopathy, and, frequently, splenomegaly. The atypical lymphocytes of infectious mononucleosis (Chapter 17) may stimulate lymphocytic lymphoma cells, since both are abnormal lymphocytic forms. Usually lymphoma cells in the peripheral blood are either more immature or more distorted than the average infectious mononucleosis (virocyte) cell. Nevertheless, since infectious mononucleosis patients are usually younger persons, the finding of lymphadenopathy and a peripheral blood picture similar to infectious mononucleosis in a patient over age 40 would suggest lymphosarcoma (if some other viral illness is not present). Suspicion is intensified if results of the Paul-Bunnell (heterophil) test (Chapter 17) are less than 1:28 or are 1:28-1:112 with a normal differential absorption pattern (two different determinations normal, done 2 weeks apart to detect any rising titer). Occasionally, rheumatoid-collagen diseases create a clinical picture suggestive of either an occult malignant lymphoma or its early stages. Phenytoin (Dilantin), smallpox vaccination, and certain skin diseases may produce a lymphadenopathy, which creates difficulty for both the clinician and the pathologist. Malignant lymphoma often enters into the differential diagnosis of splenomegaly, especially if no other disease is found to account for the splenomegaly.

The same immunologic methods used for lymphoma diagnosis can also be applied to differential diagnosis.