Pathology



Pathology Regner/Stomatis

Dr. Morgan April 11, 2001

NCI Working Formulation

Dr. Morgan reiterated that the most important details were the underlined sentences. You will be happy to know that the only underlined sentenced in this lecture occur on pg. 575 of the notes under the title of “5. Interrelationships between…” He also stated that for this lecture just know the generalizations of low, medium and high grades. The entities within each category are for our reference only. Just be able to know which diagnosis of lymphoma fall under low, medium, and high-grade categories.

Low Grade Malignancy (think small cells and follicular architecture)

A. Malignant lymphoma, small lymphocytic:

1. 4% of malignant lymphomas

2. ONLY diffuse low grade lymphoma, in general all low grade lymphomas are follicular.

3. Basically it looks like small mature lymphocytes, hence it is the tissue counterpart of CLL (chronic lymphocytic leukemia). These are the same diseases…one just presents with primarily lymph node (L.N.) involvement (A), the other (CLL) is peripheral blood and bone marrow.

4. (A) Also has a plasmacytoid variant that resembles Waldenstrom’s macroglobulinemia.

5. Immunophenotype = virgin B cells (CD5+,CD19+,CD10-)

6. Preferentially likes the L.N., but since it is essentially CLL peripheral blood and bone marrow will be involved.

Slide: Histological slide of L.N. that shows just a solid sheet of mature lymphocytes that have destroyed the normal architecture of the L.N. …(NO NODULES…for some reason nodules is synonym for follicles if talking histologically, thus NO FOLLICLES.)…Amongst these lymphocytes are larger cells with prominent nucleoli and more cytoplasm = prolymphocytes. As this cancer develops, more prolymphocytes may become prominent, and the cancer can increase in stage. (Note: prolymphocyte also means paraimmunoblast.)

B. Malignant lymphoma, FOLLICULAR, predominantly small cleaved cells:

1. < 25% large cleaved or noncleaved

2. slide: gross L.N. with small visible nodules

Slide: histo L.N. distinct follicular appearance. The cells do not look like small mature lymphocytes, but instead are small cells with cleaved or irregularly bordered nuclei.

C. Malignant lymphoma, FOLLICULAR, mixed small cleaved and large cell:

1. Mixture of small cleaved and large (cleave and/or non-cleaved) cells at 50/50 approx.

2. Obviously you will see a follicular growth pattern.

D. Odds and ends about low grade malignancies.

1. As a group, follicular lymphomas = 40 % of all malignant lymphomas.

2. 85 % exhibit a chromosomal translocation of t(14;18) involving proto-oncogene bcl-2 (B cell Lymphoma oncogene #2).

Figure 15-13 reactive vs. lymphoma follicle to see a stain of L.N. using an immunohistochemical stain for bcl-2 antigen. The cells that have bcl-2 stain brown. In a normal reactive follicle, only the mantle zone stains brown, but in the follicular lymphoma the cells in the aggregated center stain positive for bcl-2.

3. Follicular growth pattern that is >75% of cross-sectional area of L.N.= always a better prognosis regardless cell type.

4. Diffuse growth pattern that is >75% of cross-sectional area of L.N. = always a bad prognosis.

5. As cells lose their differentiation, they develop a more diffuse pattern.

6. Richter’s syndrome is a progression to a high grade large cell lymphoma.

Slides 15-11,12,13 were briefly shown (or similar slides). The captions explain what he said better than what he said.

Intermediate Grade Malignancy

A. Malignant lymphoma, follicular, predominantly large cell: (only intermediate that is follicular)

1. >50% large cleaved or noncleaved cells. From here on the cells begin becoming less well differentiated.

2. The only reason this group is not a high grade malignancy is because they are retaining the follicular growth pattern. Therefore they are behaving somewhat like B cells.

3. Uncommon, 95%. (CD4 + and /or CD8+)

C. Malignant lymphoma, small non-cleaved cell: (Burkitt’s lymphoma in the L.N.)

1. (C) Is the counterpart to ALL-L3. (Once again, (C) is found in the L.N., where as ALL-L3 is found predominantly in the peripheral blood and bone marrow.

Figure 15-16: Starry sky pattern is the most typical histological finding. It is the big pink cells (histiocytes/tingible body macrophages) that are scattered among the cells of the neoplasm on an H&E stained L.N. Except for histiocytes the small cells are very uniformed in appearance.

2. HIGHLY aggressive malignancy with the highest mitotic rate of any human malignancy.

3. The cells are growing so fast that they also rapidly die from insufficient blood supply. This process leads to the “starry sky” pattern since histiocytes then move in to clean up the necrotic debris.

4. Two sub types:

a. Typical Burkitt’s:

1. EBV is inserted into these cell’s DNA. (Epstein-Barr virus infection is part of Hx.)

2. 30% of childhood Non-Hodgkin’s Lymphoma.

3. It is typically extra-nodal.

4. African type frequently presents with a jaw mass. (Maybe because in Africa children are exposed to EBV a very young age.)

5. Non-African type presents with an abdominal mass. In females it often involves the ovary. (possibly differs from African variant because American’s exposure comes at a very later age …late teen and early 20’s)

6. ***Seldom transform into leukemia’s…typical Burkitt’s remains in L.N. and is rarely seen in the blood or bone marrow.

b. Atypical Burkitt’s = “Non-Burkitt’s”:

1. This sub-type has increased cellular heterogeneity.

2. However the immunophenotype will direct us to Burkitt’s lymphoma and the right dx.

Miscellaneous

A. Mantle cell (intermediate differentiated) lymphoma:

1. Subset of small cleaved lymphoma but is more aggressive.

2. Frequently associated with t(11:14)

Slide: Histo of mantle cell lymphoma = will see tiny atrophic follicle centers. Why? Because germinal follicles are surrounded by the small dark cells of the mantle cell zone. When the mantle cells become malignant, they will expand out from the follicle and into the follicle thereby crowding the follicle and destroying the architecture. Note: these cells do not look like normal mature lymphocytes. They have a bubbly vacuolated chromatin, but not true “dishrag” appearance.

B. Hairy Cell Leukemia:

Fig. 15-22: The cells are hairy from cytoplasmic projections. Use phase contrast to accentuate the hairs.

1. Preferentially resides in the bone marrow, but also tends to involve the spleen with massive splenomegaly.

2. NOTE: even though it is considered leukemia, it does not seem to affect the peripheral blood that often.

C. Mycosis Fungoides/Sezary syndrome:

1. These are the MALT lymphomas. (MALT = Mucosal-Associated Lymphoid Tissue)

2. Mainly line the GI tract, and with an infection the MALT will hypertrophy.

3. EX. H. Pylori causes chronic infection of the stomach mucosa. With constant MALT proliferation, these are an increased risk that one of the lymphocytes will go awry, become malignant, then clonal, and produce a lymphoma of the MALT.

4. Usually extranodal, but it is not unusual to see L.N. and MALT involved.

5. Sezary syndrome:

a. Occurs in older males.

b. Will be erythematous (similar to polycythemia vera)

c. Immunophenotype is similar to mature T cells with CD4+ predominating.

d. The cells will be medium too large with cerebiform nuclei (very convoluted).

e. Only considered Sezary syndrome when you see the cerebiform -nucleated T cells in the peripheral blood.

6. Will see skin lesions due to T cells aggregation. (Mycosis Fungoides) These can enlarge and ulcerate.

7. Will see Pautrier Microabscesses in the epidermis = little holes filled with the T cells containing the highly convoluted / cerebiform nucleuses.

D. Adult T-cell Leukemia/Lymphoma:

1. Mainly in Japan and the Caribbean.

2. Associated with the Human T Lymphocytic Virus Type – 1 (HTLV-1)

3. Skin lesions, leukemia, but more prominent lymphadenopathy, splenomegaly, and hypocalcemia.

4. Very, very aggressive with mean survival of 8 months.

Peripheral T-Cell Lymphoma

1. T cell lymphoma that has relatively mature phenotype.

2. Tend to be composed of very heterogeneous population of cells that are mainly comprised of small cleaved cells with immunoblasts and plasma cells in the background.

3. Looks very similar to a reactive pattern, but L.N. architecture is being destroyed.

4. Molecular studies show chromosomal rearrangement, and clonal ancestry.

INTERRELATIONSHIPS BETWEEN LEUKEMIA AND LYMPHOMA:

1. CLL : small lymphocytic lymphoma (SLL)

2. SLL / CLL (plasmacytiod) : Waldenstrom’s macroglobulinemia

3. T-cell ALL : lymphoblastic lymphoma

4. ALL-L3 : small noncleaved cell lymphoma (Burkitt’s lymphoma)

5. Sezary syndrome is the leukemic counterpart of mycosis fungoides with the lymph node counterpart being peripheral T-cell lymphoma

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