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

Non-Hodgkin Lymphoma: Classification

ML, small lymphocytic is always diffuse. ML,SL and CLL are indistinguishable and are almost always (>95%) of B-cell origin, expressing CD 19; CD5 (a T-associated antigen); surface IgM and/or IgD. The malignant cells are uniform small lymphocytes with scant cytoplasm. The nuclei are round with clumped chromatin. Mitoses are rare. They are monoclonal for light chains (either l or k restricted).


Occasionally, these cells have plasmacytoid or lymphoplasmacytic features.

Cases with plasmacytoid features may have a serum monoclonal IgM immunoglobulin and be associated with the clinical syndrome -Waldenstrom's macroglobulinemia.

ML,SL nearly always involves the bone marrow and commonly (>40%) involves the peripheral blood.

Transformation of ML,SL into ML, large cell type (Richter's syndrome) is rare.

Cells of ML,SL with plasmacytoid/plasma cells from patient with Waldenstrom's macroglobulinemia.

ML, follicular small cleaved cell or Follicular center lymphoma, follicular - Grade 1 is a proliferation of predominantly of small cleaved lymphocytes.

The growth pattern is follicular and the cells are always of B phenotype.

ML, F,SCC is one of the most common lymphomas (25% of all MLs).


The cells of ML, F,SCC are slightly larger than normal small lymphocytes and have an irregular clefted nucleus. The chromatin is clumped and nucleoli are indistinct. Cytoplasm is scant. A few large lymphocytes may be present, however they should not exceed more than 20% of the cells. Over expression of bcl-2 is shown at right.


Involvement of bone marrow (typical paratrabecular location) is relatively common (60-70%) with ML, follicular,SCC.

While the follicular pattern is retained for extended periods, a diffuse aggressive lymphoma develops in 25 -30% of patients.

With this progression the clinical course is accelerated and survival shortened.


ML, follicular mixed small cleaved and large cell or Follicular center lymphoma, follicular - Grade 2 includes those cases in which there is no clear preponderance of small or large cells or where the number of large lymphocytes is >5 but less than 15 cells per high power field. These show a follicular pattern of growth and are of B cell origin.

ML,follicular mixed frequently evolves to ML,large cell.


The Intermediate-Grade MLs have 5 year survival rates of 35-45%.

"New Working Formulation for Clinical Use"


D. Follicular, predominantly large cell, cleaved and/or non-cleaved - 4%
E. Diffuse, small cleaved cell - 4%
F. Diffuse, mixed, large and small cell - 7%
G. Diffuse, large cell, cleaved or noncleaved - 20%
##H. Large cell, immunoblastic -(B- or T-cell type) - 8%


* percent of all malignant lymphoma

## ML, immunoblastic is now generally placed into the intermediate-grade category along with the large cell MLs.

ML, follicular large cell or Follicular center lymphoma, follicular - Grade 3 are lymphomas in which the majority of cells within the neoplastic follicles are large cleaved or noncleaved lymphocytes. The natural history of this uncommon lymphoma (4% of all NHL) is not well known, but they frequently evolve into diffuse large cell lymphomas and seem to have a worse prognosis than other follicular lymphomas.


Mantle cell lymphoma is preferred over ML, diffuse small cleaved cell . Mantle cell ML arises in the mantle zone of secondary follicles. Small lymphocytes are arranged in a diffuse or vaguely nodular pattern. Mantle cell ML may have wide mantle zones around small atrophic follicular centers. The cells are CD 19+; CD 5+; bcl-1 +(inset at right). Generalized lymphadenopathy; splenomegaly, and peripheral blood involvement is common.


ML, diffuse, mixed small and large cell consists of both small and large-sized malignant lymphocytes. Immunologically, these are a heterogeneous group. Many T cell lymphomas as shown below are morphologically represented in this group.



ML, diffuse large cell or diffuse "histiocytic" lymphoma represents the morphologic expression of transformed lymphocytes. Most are of B-cell origin (60-80%), with some of T-cell origin (10-20%).

Large cell lymphomas are often localized and frequently form rapidly enlarging destructive masses.

Although involvement of bone marrow is relatively uncommon, ML,LC is the most frequent type of extranodal lymphoma.



Although involvement of bone marrow is relatively uncommon, ML,LC is the most frequent type of extranodal lymphoma.



Malignant lymphoma, LC diffuse and malignant lymphoma, immunoblastic are difficult for pathologists to separate.

In the REAL classification the two are placed together in the category "Diffuse large B-cell lymphoma".

In a modified NWF both lymphomas fit best into the intermediate grade category.

ML, Immunoblastic is a difuse ML with prominent plasmacytoid cell differentiation, (an eccentric nucleus with conspicuous central nucleoli and abundant basophilic cytoplasm and visible paranuclear "hof") are termed immunoblastic (B-immunoblasts).



Although ML,LC is agressive in behavior, complete remission can be achieved in approximately 75% of patients with over half of the patients free of (cured) in contrast to small lymphocytic or follicular lymphomas, which although indolent are largely refractory to treatment.


The High-Grade MLs have 5 year survival rates of 20-35%.

"New Working Formulation for Clinical Use"


I. Lymphoblastic - 4%
J. Small noncleaved cell (Burkitt's and non-Burkitt's) - 5%

* percent of all malignant lymphoma


ML, Lymphoblastic diffusely effaces the node architecture. Mitotic figures are numerous. Immunologic studies show most (80%) to be of T cell origin (expressing CD2; CD3; CD5; CD7; sometimes CD4 and CD8 together).

When mediastinal in location, lymphoblastic ML is virtually always T cell.

The neoplastic cells are mono-morphous moderate sized cells with scanty cytoplasm and round or sometimes highly convoluted nuclei.

The chromatin is fine and nucleoli inconspicuous. Mitoses are numerous indicating a rapid growth rate.



The distinction between lymphoblastic lymphoma and lymphoblastic leukemia is not always clear.

Although only 4% of NHLs of all ages are lymphoblastic, 40% of childhood lymphomasare lymphoblastic.

In 50-70% of patients the mediastinum is the primary site.



ML, small noncleaved cell or Burkitt's lymphoma is a proliferation of highly uniform cells with round to oval nuclei containing two or more prominent nucleoli. The chromatin is more clumped than in lymphoblastic lymphoma. Moderate amounts of basophilic cytoplasm are present which may contain clear lipid vacuoles.

Mitoses are numerous and a "starry-sky" pattern is often present. The "stars" are macrophages.


Burkitt's lymphomas are of B cell phenotype expressing surface immunoglobulin, CD19 and CD10 (CALLa).

The relation between Burkitt's and the normal stages of lymphoid differentiation is unclear.

Burkitt's lymphoma usually occurs in young individuals. A non-Burkitt's subtype tends to be in older individuals, more likely involves peripheral lymph nodes, and has a more pleomorphic morphology.

The lipid vacuoles seen in classic Burkitt's lymphoma/leukemia are Oil Red O positive.

Finally there are the "lymphoid" malignancies that do not fit into neat pigeon holes in the "New Working Formulation". These are perhaps best described in the REAL classification.

Marginal zone B-cell lymphoma
Primary mediastinal large B-cell lymphoma
Precursor T-lymphoblastic lymphoma/leukemia
Large granular lymphocytic lymphoma
Mycosis fungoidies/Sezary syndrome
Peripheral T-cell lymphoma
Angioimmunoblastic T-cell lymphoma; Angiocentric lymphoma; Intestinal lymphoma
Adult T-cell lymphoma/leukemia
Anaplastic large cell lymphoma, T- & Null- cell types
Angiotrophic Lymphoma
Post-transplant Lymphoproliferative Disorders


Mycosis fungoidies (MF) and Sezary syndrome are T-cell lymphomas involving the skin with widespread dissemination. The characteristic proliferating T cells are large with highly convoluted or cerebriform nuclei.

In MF the cerebriform lymphocytes infiltrate the upper dermis and epidermis, sometimes creating

'Pautrier's microabscesses in the epidermis. The lesions are erythematous with eczematoid, plaque, and tumor stages.



It is the presence of the cerebriform cells in the peripheral blood that characterizes the Sezary syndrome.

Both MF and Sezary's are clonal and usually expresses a T helper phenotype with aberrant expression of T cell antigens.



Adult T cell leukemia/lymphoma (ATL/L) is a T cell lymphoma with leukemic manifestations involving lymph nodes, skin, spleen and liver. The neoplastic circulating cells vary in size, but characteristically are large multilobulated lymphoid cells. They are T cells, nearly always T helper cells (CD 4 positive) and show aberrant expression of T cell antigens.

The ATL/L cells express CD 25 (the interleukin 2 receptor).

This is important in that CD 25 is the receptor used by HTLV1 to gain access to lymphocytes.



HTLV1 is strongly associated with ATL/L. ATL/L is localized to the Caribbean, southeastern US, and most notably southern Japan.

Hypercalcemia secondary to osteoclast stimulation is a frequent finding.

The prognosis is poor with most patients dying within 1-2 years.

Aberrant expression of T cell antigens in ATL/L with CD3 positive and CD7 negative antigen expression (CD3 +; CD7 + expected on normal T cells).



Angiotrophic Lymphoma or intravascular lymphomatosis is a rare disorder characterized by a proliferation of large lymphocytes (usually B) within small vessels. The bone marrow and peripheral blood are usually spared. The prognosis is poor, with an average survival of only 1 yr.

Because the skin and nervous system are commonly involved presenting symptoms of skin nodules, plaques, dementia and focal neurologic signs are common.

Angiotrophic lymphoma is of special interest because of the role intercellular adhesion molecules (CD44 - the lymphocyte homing receptor on lymphocytes and similar ICAMs on endothelial cells) play in the attraction and localization of lymphocytes to certain endothelial cells (High Endothelial Venules).



Angioimmunoblastic T-cell lymphoma is a T cell malignacy. Symptoms include fever, night sweats, and weight loss. Patients may have diffuse lymphadenopathy and hepatosplenomegaly, and hypergammaglobulinemia.

The lymph node shows a diffuse proliferation of immunoblasts, plasma cells, and small vessels (hence the "angio") . Eosinophils and an interstitial eosinophilic "sludgy" material are commonly observed. DNA analyses show multiple rearrangements which may correspond to small reactive clones of either B or

T cells. In some instances, one of the clones becomes malignant progressing to a full-fledged lymphoma.



Post-transplant Lymphoproliferative Disorders are intriguing lymphoproliferative lesions occurring in immunosuppressed post-transplant patients. These tumors are almost always of B lineage, but may be either monoclonal or polyclonal. If immunosuppression is withdrawn or reduced the tumor may regress.

This lesion is associated with active EBV infection and is similar to lymphoproliferative tumors observed in the X-linked mononucleosis syndrome.

Histiocytic/macrophage neoplasms include malignant histiocytosis and the relatively benign histiocytsis X or eosinophilic granuloma. The proliferating cell is large with fine chromatin and delicate nuclear folds. Eosinophils are variable in number.

These lesions are related to monocyte-macrophage cell lines and have Fc receptors and express CD1 and HLA-DR. Electron microscopy reveals Birbeck granules identical to those seen in Langerhan's histiocytes (T-zone histiocytes).

Unifocal lesions of histiocytosis X or eosinophilic granuloma (usually a focal destructive bone lesion on X-ray) are benign whereas multifocal lesions (Hand-Schuller-Christian triad) are severely disabling. The most severe of the histiocytoses is the often fatal form known as acute disseminated Langerhan's cell histiocytosis (Letterer-Siwe disease).


Extramedullary plasmacytoma is rare malignant proliferation of plasma cells. The monoclonal plasma cells may be either mature or immature in appearance. Plasmacytomas are preludes to disseminated myeloma (see Plasma Cell Disorders).

The breast mass shown below was removed because of suspected breast carcinoma. Sheets of plasma cells on a touch preparation identified it as an extramedullary plasmacytoma.



Precursor B-lymphoblastic lymphoma/leukemia

B-cell chronic lymphocytic/prolymphocytic leukemia/small lymphocytic lymphoma
Lymphoplasmacytoid lymphoma
Mantle cell lymphoma
Follicular center lymphoma, follicular - Grade I; Grade II; Grade III
Follicular center lymphoma, diffuse ?
Extranodal; Nodal?; Splenic? marginal zone B-cell lymphoma
Hairy cell leukemia
Diffuse large B-cell lymphoma
Primary mediastinal large B-cell lymphoma
Burkitt's lymphoma
Precursor T-lymphoblastic lymphoma/leukemia
T-cell chronic lymphocytic/prolymphocytic leukemia
Large granular lymphocytic lymphoma
Mycosis fungoidies/Sezary syndrome
Peripheral T-cell lymphoma
Angioimmunoblastic T-cell lymphoma; Angiocentric lymphoma; Intestinal lymphoma
Adult T-cell lymphoma/leukemia Anaplastic large cell lymphoma, T- & Null- cell types




In summary, histologic examination of a lymph node or extranodal tissue is necessary for a diagnosis to ensure proper therapy. The algorithm below may be helpful in thinking about the malignant lymphomas.


Lymphoma: Historical Overview


"Nowhere in pathology has a chaos of names so clouded clear concept as in the subject of lymphoid tumors." - Willis, l948.

Hodgkin lymphoma


Thomas Hodgkin -

first description of tumors arising in lymphoreticular tissue (tumors of the absorbent glands)



Carl Sternberg &


Dorothy Reed

identify the characteristic cell - a large binucleate or multinucleated cell with prominent eosinophlic nucleoli.




Parker classification


Rye classification

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