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L3
Malignant lymphomas
(Non-Hodgkin's lymphomas-NHLs)
ⱴ Malignancies of the lymphoid system which primarily manifest themselves outside the
bone marrow, at the sites of normal lymphoid homing
Lymph nodes
Spleen
M.A.L.T.
Anywhere
(Lymphomas outside lymph nodes and spleen are referred to as extranodal
lymphomas)
Clinical presentation
ⱴ Enlarging mass(es), typically painless, at sites of nodal tissue
ⱴ Compression, infiltration of hollow organs
o Pain, obstruction, perforation
ⱴ Interference with normal organ function-
o Solid organ infiltration- kidneys, liver, bone marrow
ⱴ Systemic symptoms
o Fever
o Night sweats
o Weight loss
ⱴ If marrow infiltrated, can have leukemic component
Pathology of Lymph Nodes
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REAL/WHO classification- backbone
ⱴ B cell neoplasms
o Precursor B cells-related to acute leukemia
o Peripheral B cell lymphomas- the majority of B cell lymphomas
ⱴ T cell and Natural Killer cell neoplasms
o Precursor T cells
o Peripheral T cell and NK neoplasms
ⱴ Hodgkin’s lymphoma
Frequency of lymphomas
Example Indolent Lymphoma: Follicular lymphoma
ⱴ Clinical
o Most common type of indolent lymphoma in US; second most common type
lymphoma overall
o Disease of adults >40 (median age 59)
o Usually widely disseminated at diagnosis, incl. bone marrow
o Will respond to “gentle chemotherapy” but will relapse
o Overall 5 yr survival 72%
o Over time, additional mutations --> progression (“transformation”) to large
cell lymphoma --> aggressive clinical course
o Although Gr.1 is most common presentation, some patients present with
predominance of large cells within follicles -->more aggressive clinical course
ⱴ Pathogenesis:
o Due to t(14;18)(q32, q21)
Upregulates expression of an anti-apoptotic protein Bcl2
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Follicular lymphoma
Epidemiology:
ⱴ FL accounts for about 20% of all lymphomas
ⱴ Highest incidence in USA and Western Europe
ⱴ Median age 6
th
decade.
rarely occurs < 20
ⱴ M/F = 1/1.7
Paediatric cases predominantly males
Sites of involvement:
ⱴ Predominantly LN, but also BM, Spleen, Peripheral blood, GIT, soft tissue, Skin
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Follicular lymphoma or Reactive hyperplasia
Low Power (Architectural)
Benign
Malignant
1. Loosely packed follicles
2. Polymorphic follicles
3. Prominent mantle zones
4. Polarized follicles
5. Preserved open sinuses
6. No capsular invasion or transgression
7. Polyclonal light chain expression
8. Non-reactive for BCL-2
1. Tightly packed follicles
2. Monomorphic follicles
3. Absent or obscured mantle zones
4. Unpolarized follicles
5. Destroyed and constricted sinuses
6. Extension into perinodal soft tissue
7. Monoclonal light chain expression
8. Reactive for BCL-2
Follicular lymphoma
Follicular lymphoma
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High Power (Cytological)
Benign
Malignant
1. A very high mitotic rate
2. Tingible-body macrophages
3. Between follicles are the usual
paracortical lymphoid cells
1. A lower mitotic rate
2. No Tingible-body macrophages
3. Between follicles atypical cleaved
cells may be found
Examples: aggressive B cell lymphoma-Diffuse large B cell lymphoma
ⱴ Clinical
Most common lymphoma- 30% NHL
Disease of adults and children, but median age 64
Limited versus widespread disease ~1:1
Presents with rapidly enlarging masses
Approximately 40% curable with aggressive chemotherapy/ stem cell
transplant
ⱴ Pathogenesis
Not as clearly defined as previous examples- several cytogenetic abnormalities
associated with large cell lymphoma, but no defining one
Diffuse Large B cell lymphoma
Pathology
ⱴ Benign equivalent- large replicating B cells of germinal center and paracortex
ⱴ Diffuse infiltration of lymph node
ⱴ Often necrosis; increased mitotic rate
ⱴ Cytology: Oval or cleaved nucleus with vesicular chromatin and 1-3 nucleolus
ⱴ Nucleus larger than that of reactive macrophage
ⱴ Several cytologic subtypes initially felt to have differing clinical behavior.
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Burkitt's lymphoma
ⱴ
Clinical
3% lymphomas
o Disease of adults and children- median age 31
o Initially recognized in Africa by Thomas Burkitt
Association with Epstein Barr virus infection
Localization in jaw
o In US, usually presents in ileocecal region of children
o 1/3 of all childhood lymphomas
o Earlier, very aggressive and rapidly fatal
Now, ~70-80% children curable
40% of adults
ⱴ
Pathogenesis:
o t(8;14), producing upregulation of myc oncogene, a cell cycle regulation
gene
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ⱴ
Pathology
o Benign equivalent is replicating small noncleaved cell of germinal center:
o Diffuse infiltration of lymph node
o Very high mitotic rate,
o Attracts macrophages to phagocytize> starry sky pattern at low power
o Cytology: round nucleus, smaller than that of reactive macrophage
Vesicular chromatin and 2-5 nucleoli
o Immunophenotype:
Positive: Monoclonal light chain, CD19, CD10
Negative: CD5
Mantle cell lymphoma
Clinical
ⱴ 6% lymphomas
ⱴ Disease of adults (median age 63)
ⱴ Usually widely disseminated
ⱴ Poor response to all attempted therapies,
ⱴ ? curable with transplant
ⱴ 5yr survival 27%
Pathogenesis
ⱴ Due to t(11;14)
ⱴ Upregulates Bcl1 (cyclin D1), a cell cycle regulator
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ⱴ MCL accounts for 3-10% of NHL
ⱴ Middle age – older patients
ⱴ Male > Female
ⱴ LN +/- Spleen, BM, Peripheral blood
Extranodal sites : GIT and Waldeyer’s ring
ⱴ Prognosis poor, median survival 3-4 years
ⱴ Genetic hallmark: t(11;14)(q13:q32) CCND1/1GH translocation -> Cyclin D1 over-
expression
ⱴ
CD20,CD19, CD79a, PAX5 ,
CD5 & Cyclin D1 positive
ⱴ CD23 negative
CLL/SLL
ⱴ Most common leukaemia in adults in the western world 6.7% of all NHL biopsies
ⱴ Indolent Clinical course
ⱴ Generalised lymhadenopathy + leukaemic phase
ⱴ Diffuse growth of small lymphocytes with prolymphocytes and paraimminoblasts in
Proliferation Centres
ⱴ Trisomy 12 (33%), 13q (25%)
ⱴ Transformation to large cell lymphoma in 5% of cases
ⱴ
Positive for PAX5, CD22, CD19, CD20,
CD5, CD23 and CD79a
ⱴ Cyclin D1 negative
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Peripheral T cell lymphomas
ⱴ Predominantly leukemic/disseminated
o T-cell prolymphocytic leukemia
o T-cell large granular lymphocytic (LGL) leukemia
o NK cell leukemia
o Adult T-cell leukemia/lymphoma
ⱴ Predominantly nodal
o Angioimmunoblastic T-cell lymphoma
o Peripheral T-cell lymphoma unspecified
o Anaplastic large cell lymphoma, T/null-cell
ⱴ Predominantly extranodal
o Mycosis fungoides
o Sezary syndrome
o Primary cutaneous CD30+ T-cell lymphoproliferative disorders
o Subcutaneous panniculitis-like T-cell lymphoma
o NK/T cell lymphoma, nasal and nasal-type
o Enteropathy-type intestinal T-cell lymphoma
o Hepatosplenic T-cell lymphoma
Key points regarding T cell lymphomas
ⱴ Clinical
o Represent 20% all lymphomas
o More often extranodal than B
Can involve skin, midline facial area, liver
Very characteristic clinical presentations
o Most diseases bad: high stage, and poorer response to therapy than B cell
lymphomas of all grades
ⱴ Pathogenesis:
o Characteristic cytogenetic findings associated with several types
Anaplastic large cell lymphoma- t(2;5): ALK1 gene
Hepatosplenic T cell lymphoma- Isochromosome 7
ⱴ Pathology
Cytologic features not as predictive of behavior as B cell lymphomas
Anaplastic large cell lymphoma --> better prognosis than most
indolent B cell lymphomas- 77% 5 year survival
Mycosis fungoides, indolent cutaneous lymphoma, incurable, but with
long clinical course
Immunophenotypic studies frequently demonstrate
Loss of normal T cell associated antigens
Antigens associated with Natural Killer cell function
Immunology absolutely necessary to recognize
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Clinical presentation
ⱴ Enlarging mass(es), typically painless, at sites of nodal tissue
ⱴ Obstruction, ulceration of hollow organs- pain, perforation
ⱴ Interference with normal organ function-
o Solid organ infiltration- kidneys, liver, bone marrow
ⱴ Systemic symptoms
o Fever
o Night sweats
o Weight loss
ⱴ If marrow infiltrated, can have leukemic component
Clinical staging of lymphomas
ⱴ Defines extent of disease; determines therapy and prognosis
ⱴ Based on physical, radiologic examination, bone marrow biopsy and aspiration
ⱴ Ann Arbor Staging system
ⱴ B symptoms- fever, weight loss > 10% body weight, night sweats
Staging table
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Mubark A. Wilkins
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