Lymphoproliferative disorder cases - App Flashcards
Lymphoid Hyperplasia
- Reactive lymph node (LN) enlargement
(hyperplasia) occurs in a wide variety of clinical conditions
– Depending on the underlying etiology, one or more
LN compartments may be preferentially stimulated - Disorders associated with activation of B-cells give rise to hyperplasia of the secondary follicles (germinal centers)
- Disorders associated with T-cell activation give rise to
hyperplasia of the paracortical (interfollicular) regions - In some cases, a more diffuse hyperplasia, involving both B and T cell zones of the lymph node can be seen
reactive patterns/conditions
- Acute suppurative lymphadenitis
- Reactive follicular hyperplasia
- Interfollicular/paracortical (T-cell zone) hyperplasia
- Dermatopathic lymphadenopathy
- Lymphoid hyperplasia involving nonlymphoid tissue
Acute Suppurative Lymphadenitis
- Typically seen in cases of acute bacterial infections (common bacteria: Staph and Strep)
- Lymphatic drainage secondarily involves regional lymph nodes
- Histologically, there is a neutrophilic infiltrate within the nodal sinuses and parenchyma , sometimes with abscess formation
- Often associated with follicular hyperplasia
Reactive Follicular Hyperplasia
- A non-specific pattern seen in many clinical conditions (B-cell activation)
- Secondary lymphoid follicles are increased in number and in size
- Reactive 2° follicles are characterized by:
- Polarity of germinal centers (segregation of smaller and larger cells within germinal centers)
- Tingible body or “starry sky” macrophages within germinal centers
- Prominent/well formed mantles of small lymphocytes around germinal centers
Reactive 2° follicles in reactive follicular hyperplasia is characterized by:
- Polarity of germinal centers (segregation of smaller and larger cells within germinal centers)
- Tingible body or “starry sky” macrophages within germinal centers
- Prominent/well formed mantles of small lymphocytes around germinal centers
BCL2 immunostain
- BCL2 is an anti- apoptotic protein
- Reactive GCs are BCL2 negative
- Neoplastic GCs (follicular lymphoma ) often stain positive for BCL2
Interfollicular/Paracortical Hyperplasia
- Non-specific pattern (T-cell activation)
- Seen with many viral infections (EBV, CMV,
varicella-zoster, etc), and following vaccinations - May occur with use of drug Phenytoin (Dilantin)
- Histologically characterized by:
– Mixture of small and larger activated lymphocytes,
some withprominent nucleoli (immunoblasts)
– proliferation of interdigitating dendritic cells (IDCs) in
paracortex (antigen presenting cells for T cells)
Dermatopathic Lymphadenopathy
- Reactive changes in LN due to a variety of
chronic inflammatory dermatoses - Drainage of material (melanin, hemosiderin) to
regional LNs, which incites an immunologic
reaction - Histologically, this reaction is characterized by
interfollicular hyperplasia with a proliferation
of pale-staining macrophages, some of which
may contain melanin or hemosiderin pigment
Malignant Lymphomas - overview
- Lymphomas are neoplastic disorders derived from
lymphocytes - Primary sites of involvement are LNs and other lymphoid tissues, although extranodal tissue may also be involved
- Routine morphology (H&E sections) is the starting point in the evaluation for lymphoma but often not definitive
- Low power examination is performed to determine
whether the normal nodal architecture is intact or effaced - Effacement of architecture is a consistent finding in
lymphoma - Flow cytometry, immunohistochemistry, FISH, molecular, and cytogenetic studies are important/necessary adjuncts in diagnosis of lymphoma
Malignant Lymphomas - grouping/classification
- Lymphomas can be grouped into two main categories:
1) Hodgkin lymphoma
2) Non-Hodgkin lymphoma - Hodgkin lymphoma (there are several different subtypes):
- Derived from germinal center B-cells
- Fairly homogeneous in clinical presentation/progression
- Non-Hodgkin lymphomas (very heterogeneous group):
- May be derived from B-cells, T-cells, or NK cells
- Widely varying clinical presentations and overall prognoses
- There is also a group of neoplasms derived from plasma cells
- Prototype = plasma cell myeloma (multiple myeloma)
- One way to organize all the types of lymphoproliferative
disorders is according to their cell of origin (see next slide)
CASE #1 (1/1)
A 19 year-old boy presents to the ER with
progressive shortness of breath, which now
interferes with his ability to play sports.
Initial labs reveal a leukocytosis. The figure
below shows a chest x-ray obtained at the
time of presentation.
- What do you think about the history/imaging?
- Describe the imaging findings
- What do you think about the leukocytosis?
- What should be done next? What is easiest?
- Suggest additional studies/procedures that
may help establish a definitive diagnosis.
Describe the cytomorphology of the blood smear:
- Cell size (big or small) and shape
- Cytoplasm (quantity and quality)
- Nuclear chromatin (coarse or fine, nucleoli?)
- N:C ratio
- Do they look mature or immature?
- Myeloid or lymphoid (can we tell?)
What about the mediastinal mass?
- Do you think it is related to the blood findings?
- What should we do to evaluate it?
- Hint: this is a pathology lecture.
- That’s right! Examine a biopsy.
- Beyond H&E, what special studies could
be used to help characterize/diagnosis
the lesion?
Chest x-ray showing large mediastinal mass. CBC reveals leukocytosis with many circulating large atypical cells seen on peripheral blood smear. To summarize, we can say that there is a circulating monotonous population of large immature cells with scant agranular basophilic cytoplasm and occasional hand mirror forms (possibly lymphoblasts). Note that some of the lymphoblasts have irregular nuclear features, typical of T-cell lymphoblastic
leukemia/lymphoma (T-ALL).
Figure on the right shows the microscopic appearance of a biopsy obtained from the mediastinal mass
showing a monotonous proliferation of immature cells (lymphoblasts) with occasional interspersed
“starry sky” macrophages.
How can we definitively characterize the neoplastic cell population (myeloid vs. lymphoid, B vs. T etc)?
What studies/techniques could be used?
**Flow cytometry **is very useful and quick way to immunophenotype the tumor cells: Here are a few
selected flow scatter plots (the tumor cell population is in green, sCD3 = surface CD3, cCD3= cytoplasmic
CD3). Flow cytometry results (lymphoblasts are in green). The lymphoblasts are positive for CD1a and
cytoplasmic (but not surface) CD3 and also co-express CD4 and CD8. They are positive for TdT
(terminal deoxynucleotidyl transferase). This phenotype is typical of precursor T cells (cortical
thymocytes). In addition (not shown), the lymphoblasts may also be positive for CD34, and CD10.
FINAL DX:
Precursor T-cell acute lymphoblastic
leukemia/lymphoma
CASE #2
A 24 year-old man presents with increasing shortness of breath and right neck swelling. The following slides show the appearance of the patient and his initial chest imaging studies.
What next?
* What do you think about the history and the
patient’s appearance/imaging?
* Describe the imaging findings (why is he
short of breath?)
What should be done next?
* Suggest additional studies/procedures that
may help establish a definitive diagnosis.
Describe the pathologic findings
- Describe the gross appearance of the LN
- Describe the low mag appearance of LN
- Describe the high mag appearance of LN infiltrate:
- Tumor cell cytomorphology
- Background cellularity
- Suggest a possible diagnosis and recommend
confirmatory special studies
Right cervical lymphadenopathy.
Chest x-ray and (left) and MRI (right) showing anterior, superior mediastinal mass.
Lymph node biopsy (bisected). Note the size, vague nodularity, and areas of sclerosis.
Low power view of lymph node showing effaced nodal architecture with nodular areas and intervening
sclerosis (collagen fibrosis).
Med power - scattered large atypical cells with prominent nucleoli in a mixed inflammatory (small lymphocytes, eosinophils, plasma cells) background
higher power view demonstrating several typical Reed-Sternberg cells
FINAL DX: Classical Hodgkin lymphoma, nodular sclerosis subtype
CASE #3: A 59 year-old man presents with mild weakness
and fatigue. Physical examination demonstrates
palpable adenopathy in the cervical, axillary, and
inguinal regions.
What should we do?
An axillary lymph node was biopsied. Describe its
gross and histologic appearance. Any ideas?
Bisected lymph node showing vaguely nodular cut surface.
**Lymph node **showing effacement of the normal lymph node architecture by a proliferation of numerous
secondary lymphoid follicles. Note the lack of polarity in the back to back germinal centers and their
attenuated follicular mantles. “Starry sky” macrophages are also absent.
Higher magnification of germinal center showing predominantly small lymphocytes with irregular nuclei (centrocytes) and occasional larger lymphoid cells with multiple peripherally located nucleoli (centroblasts).
**Flow cytometry **on a portion of lymph nodal tissue shows that the vast majority of B-cells (CD19 and
CD22 positive cells) are positive for CD10 and surface kappa light chain (kappa light chain restricted).
A, CD20 immunostain shows that CD20 + B cells are present both within and between follicles ( inset). B,
Immunostaining for CD10. Note positive staining of lymph follicles, indicating the cells are of germinal
center origin. C, Bcl-6 is another marker that will stain cells of germinal center origin. D, Immunostain
for BCL2 in follicular lymphoma shows strong, uniform positivity within follicles.
Karyotype in follicular lymphoma showing a reciprocal translocation between chromosome 14 (IgH gene) and chromosome 18 (Bcl-2), resulting in upregulation of the Bcl-2 gene, which protects the lymphoma cells from undergoing apoptosis.
Gross (left) and histologic (right) pictures of a spleen in a case of follicular lymphoma showing diffuse
involvement of the splenic white pulp.
FINAL DX: Follicular lymphoma
CASE #4
A 62 year-old man presents with generalized
lymphadenopathy. CBC evaluation demonstrates a
leukocytosis with an absolute lymphocytosis. The
images below shows the appearance of the
patient.
What should we do?
What would be quickest and easiest?
Patient photo showing extensive cervical and axillary lymphadenopathy.
Periphral blood smear from patient showing proliferation of small mature lymphocytes with smudge cells, consistent with chronic lymphocytic leukemia (CLL).
peripheral smear prepared with albumin, fragile nature of the CLL cells = smudged during smear preparation. Incubation with bovine serum albumin prior to smear preparation allows better preservation of CLL cells.
Small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are the same disorder and patients often demonstrate simultaneous involvement of lymph nodes (SLL) and bone marrow/blood (CLL).
Appearance of a biopsied axillary lymph node. Cross-sections of resected lymph node showing “fish flesh” appearance, consistent with involvement by lymphoma.
The series of images below show the microscopic appearance of the biopsied axillary lymph node from low to high power. Does the nodal architecture appear effaced, and if so how (nodular or diffuse?): The lymph node shows effacement of the normal architecture by a diffuse (or perhaps vaguely nodular) infiltrate of small lymphocytes.
high power, we see that the infiltrate is composed chiefly of small, round, mature lymphocytes,
consistent with small lymphocytic lymphoma (SLL). Occasional larger lymphocytes are present (arrow).
Typical flow cytometry results for SLL/CLL. Lymphoma cells express B cell markers (e.g. CD19, CD20, and CD22), co-express CD5 and CD23, and show surface light chain restriction.
Spleen. Similar to follicular lymphoma, SLL/CLL when it involves the spleen shows diffuse infiltration of the splenic white pulp.
FINAL DX:
Chronic lymphocytic leukemia/Small
lymphocytic lymphoma (CLL/SLL)
CASE #5
A 58 year old woman presents with a rapidly
enlarging mass in her right axilla. The following
image shows the appearance of a biopsied axillary lymph node.
Describe the gross findings.
**Resected matted lymph nodes showing whitish, “fish flesh” appearance.
touch preparation was made in lieu of frozen section at the time of surgery
series of images below shows the microscopic appearance of the biopsied axillary lymph nodes from
low to high power.
Describe the cytomorphology:
* Nodal architecture (intact or effaced)
* Growth pattern (nodular or diffuse)
* Cell size (big or small) and shape (regular or
irregular)
* Cytoplasm (quantity and color)
* Nuclear chromatin (coarse or fine, nucleoli?)
* N:C ratio (high or low)
* Differential diagnosis?
* Additional special studies needed?
High magnification of lymph node showing diffuse infiltration by large atypical lymphoid cells, consistent
with diffuse large B-cell lymphoma. Compare the size of the tumor cells to background small T-cells, RBCs, endothelial cells, and granulocytes.
How can we show that the large neoplastic cells are B-cells and that they are clonal?
CD20 and PAX5 immunohistochemical stains show that the tumor cells are B-cells. The clonal IGH gene
rearrangement result proves the B-cells are clonal/neoplastic. A high Ki67 index (greater than 40%
positivity) proves that the lymphoid infiltrate is high grade (aggressive).
Splenic involvement by diffuse large B-cell lymphoma showing a large tumor nodule, which effaces the normal splenic architecture.
FINAL DX:
Diffuse Large B-cell Lymphoma (DLBCL)
CASE #6
A 52 year-old man presents with fever, night
sweats, and unexplained weight loss. Physical
examination demonstrates cervical and inguinal
adenopathy. As part of his evaluation, he
undergoes colonoscopy. The following images
shows the typical appearance of the colon in this
patient’s disorder.
Gross appearance of colon containing numerous polypoid lesions (lymphomatoid polyposis).
low power microscopic appearance of a biopsy of an intestinal lesion:
Terminal ileum biopsy showing diffuse infiltration of the lamina propria and submucosa by lymphoid cells. A CD20 immunohistochemical stain reveals that the lymphoid infiltrate is composed chiefly of B- cells.
The patient also underwent a lymph node biopsy. The lymphoid infiltrate looks very similar to the bowel
lesion. The series of images below shows the microscopic appearance of the biopsied lymph node from low to high power.
Describe the cytomorphology
* Nodal architecture (intact or effaced)
* Growth pattern (nodular or diffuse)
* Cell size (large, small or medium)
* Nuclear contour (round or irregular)
* Differential diagnosis?
* Additional special studies needed?
**The lymph node shows **effacement of the normal nodal architecture. Higher magnification shows infiltration by medium-sized lymphocytes, which show somewhat irregular nuclear morphology, consistent with mantle cell lymphoma. Note the presence of occasional hyalinized vessels.
Flow cytometry results for mantle cell lymphoma. The lymphoma cells express B cell markers (e.g. CD19,
CD20, CD22). Similar to CLL/SLL, the lymphoma cells aberrantly express CD5, but unlike SLL/CLL they do not express CD23. The lymphoma cells also show surface light chain restriction.
Karyotype results showing reciprocal translocation between chromosomes 11 (Bcl-1 gene) and chromosome 14 (IgH gene). This translocation causes upregulation of Bcl-1, which facilitates progression of the lymphoma cells through the cell cycle.
FINAL DX:
Mantle Cell Lymphoma
CASE #7
A 29 year old man presents with a very rapidly
enlarging neck mass. On physical examination he
is noted to have a soft ball size left neck mass. An
incisional biopsy of the left neck mass is
performed. The images below show the histologic
appearance of the neck mass.
Describe the cytomorphology
* Growth pattern (nodular or diffuse) and tissue involved
* Cell size (large, small or medium)
* Nuclear contour (round or irregular)
* Nuclear chromatin
* Differential diagnosis?
* Additional special studies needed?
The microscopic images above show extensive infiltration of skeletal muscle by a high grade lymphoid
infiltrate of medium-large sized lymphoid cells. Note the presence of numerous mitoses, foci of single cell
necrosis/apoptosis, and scattered “starry sky” macrophages.
What is your differential diagnosis? What
ancillary studies should be done to confirm the morphologic impression?
Flow cytometry reveals that the lymphoma cells express B cell markers (e.g. CD19), co-express CD10
(consistent with a germinal center origin), and show surface lambda light chain restriction.
perform immunohistochemistry on tissue sections
karyotype showing reciprocal translocation between chromosomes 8 (c-myc gene) and
chromosome 14 (IgH gene) (upper right). This translocation causes upregulation of c-myc, which
provides numerous beneficial effects to the lymphoma cells. Some cases of Burkitt lymphoma have
alternate translocations, including t(2;8) and t(8;22), which involve c-myc and the kappa and lambda
light chain genes, respectively.
Imprint smear often show large atypical cells with deeply basophilic, vacuolated cytoplasm, and salt &
pepper chromatin highly characteristic of Burkitt lymphoma.
Burkitt lymphoma frequently shows extranodal involvement by tumor and often involves the GI tract.
Here is a gross picture of Burkitt lymphoma involving the bowel wall in another patient
FINAL DX:
Burkitt Lymphoma
CASE #8
A 45 year-old woman presents with upper
abdominal pain. She undergoes endoscopy, which
demonstrates gastritis, as well as an antral mass.
The following image shows the low (left) and high (right) power appearance of a gastric biopsy.
Low power view of a gastric biopsy showing diffuse infiltration of the lamina propria and submucosa by small mature lymphocytes.
Higher magnifications of gastric biopsy showing submucosal infiltration by small, mature, somewhat irregular lymphocytes with abundant clear cytoplasm. The lymphoma cells infiltrate the gastric glands forming lympho-epithelial lesions, characteristic of extranodal marginal zone lymphoma (MALToma).
immunostain for CD20 shows that the lymphoid infiltrate is composed of sheets of B-cells.
high magnification of the surface epithelium in such cases of gastric MALToma often shows numerous rod-like bacteria, consistent with Helicobacter pylori, confirmed by immunostain for H. pylori.
FINAL DX:
Extranodal marginal zone lymphoma (MALToma).
CASE #9
A 62 year-old man presents with the whole body
skin rash shown below. Physical examination also
demonstrates inguinal and axillary adenopathy.
What should we do?
What would be quickest and easiest?
Low power view of a skin biopsy showing extensive superficial dermal infiltration by lymphocytes, which focally extend into the overlying squamous epithelium (epidermotropism).
Higher magnification of skin biopsy showing a focal collection of atypical lymphocytes with irregular
(cerebriform) nuclei within the squamous epithelium, called a Pautrier microabscess, characteristic of
mycosis fungoides.
Mycosis fungoides is a common type of cutaneous T-cell lymphoma. Immunohistochemical stains for CD3 and CD4 on the skin biopsy.
How do we know this a lymphoproliferative disorder and not just a bad rash?
Clonal T-cell receptor gene rearrangement and/or aberrant antigen expression (e.g. CD7 loss)
Blood smear showing atypical lymphoid cells with “cerebriform” nuclear morphology, characteristic of Sezary syndrome (leukemic phase of mycosis fungoides). The atypical lymphoid cells in the skin and blood are clonal CD4-positive T cells, despite the name mycosis fungoides.
FINAL DX:
Mycosis fungoides/ Sezary Syndrome
CASE #10
A 40 year old man presents with anemia,
lymphadenopathy, and hepatomegaly with
multiple liver masses. A CT scan of the abdomen is
seen below.
The series of images below shows the microscopic appearance of the liver biopsy at medium to high
magnification.
The infiltrate is composed of sheets of large atypical lymphoid cells with highly irregular often bizarre nuclei (pleomorphic or anaplastic are good adjectives to use here). Occasional cells with horseshoe shaped nuclei (hallmark cells) and multinucleated cells are present as well as scattered mitotic figures and foci of single cell necrosis/apoptosis.
Describe the pathologic findings
* Do you see any normal liver?
* How would you describe the infiltrate (diffuse or nodular?)
* Tumor cell cytomorphology (small or large cells, regular or bizarre nuclei, etc.)
* Is the lesion is indolent or aggressive?
* Suggest a possible diagnosis and recommend additional special studies
Flow cytometry performed on a portion of the liver biopsy tissue was nonspecific/nondiagnostic.
Immunohistochemical studies performed on the liver biopsy show the following:
The tumor cells are derived from T-cells and express CD2, CD4, CD30 (strong and diffuse), and ALK1; but are negative for CD3, CD8, and CD20. The Ki67 proliferative rate is also quite high as might be expected from the presence of numerous mitotic figures. The combined morphologic and immunohistochemical findings are diagnostic of ALK positive anaplastic large cell lymphoma. Cytogenetic analysis of ALK positive anaplastic large cell lymphoma often reveals t(2;5), a reciprocal translocation between chromosome 2 (ALK) and chromosome 5 (NPM1). ALK positive anaplastic large cell lymphoma has a better prognosis than the ALK negative variant and tends to occur in younger patients.
FINAL DX:
Anaplastic large cell lymphoma, ALK positive
CASE #11
A 59 year-old man presents with low back pain. On
physical examination, there is no palpable
adenopathy or organomegaly. A CBC demonstrates
anemia and thrombocytopenia. As part on his
evaluation, he has a skeletal survey performed. His
skull x-ray is shown below.
What now?
* What do you think about the X-ray and SPEP?
* What is causing the patient’s anemia and thrombocytopenia?
* What should be done next?
* Suggest additional studies/procedures that may help establish a definitive diagnosis.
Skull x-ray showing multiple lytic bone lesions.
Protein electrophoresis showing monoclonal band in the gamma region, which consists of IgG kappa
protein.
Bone marrow aspirate smears showing an infiltrate of atypical plasma cells, consistent with plasma cell myeloma (also known as multiple myeloma). Note that some plasma cells are large with very prominentnucleoli (plasmablasts).
The plasma cell infiltrate can also be seen in the bone marrow core biopsy. Note the plasmablasts.
Plasma cells are difficult (but not impossible) to analyze by flow cytometry. We can also characterize the plasma cell infiltrate by immunohistochemistry. The plasma cell are CD138 positive, weakly positive for CD56 (aberrant expression), and kappa light chain restricted.
FINAL DX:
Plasma cell myeloma
