Blood and BM Path Chapter 29 - Lymphoma Flashcards
In which cases of suspected lymphoma do we also do a bone marrow biopsy?
Almost every case of Non-Hodgkin lymphoma, and in some patients with Hodgkin lymphoma
Atypical lymphoma presentations
A lot of lymphomas present as unexplained progressive lymphadenopathy, but many will present as:
- Unexplained cytopenias
- Paraproteinemia
- Immunodeficiency
- Unexplained B symptoms (more common in HL)
Reactive germinal centers in the bone marrow
Rare, but more common in older patients and suggestive of rhumatologic process (often RA) or a systemic inflammatory disorder.
Characteristics of lymphoma in the bone marrow
Often paratrabecular, where you should never see normal lymphoid tissue in the BM.
May also be dispersed between marrow elements, whereas normal bone marrow lymphoid tissue should be well circumscribed.
Even when you have tissue necrosis due to lymphoma in the bone marrow, ___ is still a very useful stain
Even when you have tissue necrosis due to lymphoma in the bone marrow, CD20 is still a very useful stain
In a necrotic section of what was once a B-cell lymphoma, CD20 will stain the “ghosts” of former malignant B cells.
Unfortunately, this doesn’t work so well for T-cell lymphomas
B lymphoblastic leukemia/lymphoma with BCR-ABL1
May arise from pre-existing CML
t(9;11)
B lymphoblastic leukemia/lymphoma with MLL rearrangement
t(v;11q23)
B lymphoblastic leukemia/lymphoma with TEL-AML / ETV6-RUNX1
t(12;21)
B lymphoblastic leukemia/lymphoma with hyperploidy
B lymphoblastic leukemia/lymphoma with hypoploidy
B lymphoblastic leukemia/lymphoma with IGH-IL3
t(5;14)
B lymphoblastic leukemia/lymphoma with E2A-PBX1 / TCF3-PBX1
t(1;19)
How can you tell if you’re looking at an LPL or a B-CLL/other BCL with plasmacytic differentiation?
It can be tough. Molecular testing for MYD88 mutation is really helpful here. Some other features are:
- Increased mast cells (common in LPL)
-
Proliferation center presence vs absence (absent in LPL, present in many other types of lymphoma)
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This is a BM trephine biopsy from a patient with cytopenias. Recitulin staining is WHO grade 3 and the marrow has been diffusely replaced by this infiltrate, which stains CD20+.
What is the diagnosis?
This is classic Hairy cell leukemia.
Replacement of much of BM with almost complete loss of BM fat is very common on presentation for these patients. They may or may not have circulating hairy cells.
Note the widely spaced, abundant, pale cytoplasm and the irregular nuclei with occasional bilobed nuclei.
Reactive mast cells and plasma cells are often also present. Neutropenia is the most common cytopenia to be seen, as for whatever reason myeloid cells are most affected in HCL.
Stain with CD25 and CD123 to confirm the diagnosis. CD68 with dot-like cytoplasmic pattern can also confirm. TRAP can too, but not with as high sensitivity.
Hairy cell leukemia variant (HCLv)
Quite rare, more common in Asian populations
Kind of a misnomer, as it is clinically, immunophenotypically, and genetically distinct from HCL.
Patients present w/ splenomegaly (like HCL), anemia is common but neutropenia is rare. There are usually abundant circulating cells (more of a leukemia than lymphoma). Like HCL, HCLv cells have cytoplasmic projections on cytology, but they also have prominent nucleoli like in B-PLL.
Immunophenotype: CD25-, CD123-, CD11c+, CD103+, FMC7+
Splenic marginal zone lymphoma
Typically presents with splenomegaly +/- hilar adenopathy. Associated with Hepatitis C. Paraprotein may be present, usually IgM, but not as frequently as in LPL and at a lower titer.
Pathologically, there is widespread involvement of the splenic white pulp, which gives a miliary appearance to gross splenic specimens. Germinal centers are atrophic and crushed by the expanded mantle zone, which is full of slightly large, plasmacytoid or monocytoid cells. The cells can also often be seen near the red pulp capillaries.
Bone marrow involvement may include nodular, interstitial, paratrabecular, and sinusoidal patterns.
SMZL lacks any characteristic recurrent genetic anomalies, but molecular studies are helpful as rule-outs for alternative diagnoses.
Immunophenotype: CD19+, CD20+, surface IgM+, often co-express surface IgD, CD5-, CD10-. Sometimes with CD23+ and CD11c+.
Patient presents with cytopenias. They are found to have splenomegaly on exam. A low-titer IgM paraprotein is detected. Peripheral smear shows these “other” cells.
What is the diagnosis?
These are circulating villous lymphocytes, characteristic of splenic marginal zone lymphoma or rarely splenic diffuse red pulp small B-cell lymphoma
Flow cytometry and molecular/cytogenetics are very helpful in making the diagnosis by process of elimination, but there are not many specific features of SMZL.
Splenectomy and tissue histology is the best way to make the diagnosis confidently, however this is often not a good clinical option.
Patient presents with splenomegaly and cytopenias. Due to their critical cytopenias and concern for splenic sequestration, splenectomy is preformed. Shown is a slice of gross specimen from the spleen.
What is the diagnosis?
The most likely diagnosis is splenic marginal zone lymphoma
The miliary texture is highly characteristic of SMZL on gross
Splenic diffuse red pulp small B-cell lymphoma
Presents with splenomegaly and peripheral blood B cell lymphocytosis, sometimes with cytopenias.
Unlike SMZL, splenic involvement is diffuse, involving/replacing the red pulp. Similar to SMZL, circulating villous lymphocytes may be present, but will also have an unusually basophilic cytoplasm.
Bone marrow involvement is universal, but hard to detect on trephine biopsy because it is exclusively sinusoidal (shown). CD20 staining will highlight single file lines of cells in sinusoids. This often occurs in SMZL as well, but SMZL will also have other BM involvement.
Sometimes carries a characteristic translocation: IGH-PAX5, t(9;14)
The immunophenotype is similar to HCLv (it is believed these diseases may be on a spectrum biologically): CD25-, CD123-, CD11c+, CD103+, FMC7+
Extranodal marginal zone lymphoma - MALT type
Very indolent lymphoma with a good prognosis overall. Usually arises from GI MALT tissue, but can arise from salivary, pulmonary, orbital, or urogenital mucosa. Often arise in the setting of infection-induced MALT hyperplasia.
On low power, tumors appear to be disorganized follicles in a submucosal space that may have strands of cells invading into the mucosa. Cells are centrocyte-like with a tendency to infiltrate epithelia and form lympho-epithelial lesions. Can have plasmacytoid or monocytic differentiation. ~30% of cases involve marrow, usually with a nodular pattern.
Multiple characteristic translocations have been described: t(11;18) API2-MALT1, t(14;18) IGH-MALT1, t(3;14) IGH-FOXP1, t(1;14) IGH-BCL10
Centrocyte vs centroblast morphology
Nodal marginal zone lymphoma
Indolent and usually presents with advanced disease, often involving peripheral and para-aortic adenopathy.
Histologically, has disorganized follicular architecture similar to secondary colonization of a LN by MALT lymphoma, with expansion of the interfollicular space due to invasion of pale cells with an abnormal amount of cytoplasm. On high power, the infiltrate is heterogeneous, including centrocyte-like cells and others showing marginal zone cell or plasmacytoid differentiation.
Immunophenotypically, N-MZL is bland and indistinguishible from MALT lymphoma. If you’re lucky, it rarely expresses CD43 or CD23, which are helpful hints. CD5, CD10, and cyclin D1 will be negative.
Genetically, trisomies 3, 7, and 18 are common. You will not find MALT translocations associated with N-MZL.
Nodal MZL cells vs monocytoid B-cell hyperplasia
Monocytoid B-cells are medium-sized cells that are quite similar to hairy cells in histologic sections, having oval or bilobed nuclei and abundant, clear cytoplasm
On the other hand, infiltrates in nodal MZL are usually heterogeneous, including centrocyte-like cells and others showing marginal zone cell or plasmacytoid differentiation
Intravascular Large B Cell Lymphoma
In this rare lymphoma, neoplastic cells are rarely recognized in blood or BM aspirate. They can be found on histologic biopsy limited to the arteries and sinusoids. CNS involvement is present in ~80% of cases.
They are large and anaplastic, resembling cells of Hodgkin or anaplastic large cell lymphoma
They show varying combinations of CD5, CD10 and IRF4/MUM1 expression in addition to expressing CD20 and other pan-B cell markers
There is no known genetic etiology, in part because cases are so rare.
Extranodal T/NK cell lymphoma, nasal type
Much more common in Asia than elsewhere and is strongly associated with EBV infection. An intravascular variant also exists.
Classical presentation is with a necrotizing mid-facial neoplasm, however these lymphomas may occur at other body sites. Disease activity can be monitored by the circulating EBV DNA. May occur in the setting of immunosuppression.
Histologically, mucosal sites show ulceration. The lymphomatous infiltrate is diffuse and permeative, often extending to involve the dermis and even epidermis. Inflammatory features frequently mask the presence of neoplastic cells, and so diagnosis can be diffcult. Coagulative necrosis and apoptotic bodies are common findings. On Giemsa-stained touch preparations, azurophilic granules are commonly detected.
Characteristic immunophenotype: CD2+, CD5−, CD56+, sCD3−, cCD3 epsilon +. CD56 is nonspecific to other NK neoplasms, so don’t rely on this alone. EBER ISH should basically always be positive.
Enteropathy-associated T-cell lymphoma
Usually presents in adults with small bowel obstruction due to constricting tumor or with perforation due to tumor ulceration
The neoplastic cells are medium-sized or large, with a cytotoxic T-cell phenotype, often associated with extensive tissue necrosis underlying the formation of ulcers.
Most cases show background histologic features of gluten-sensitive enteropathy in non-neoplastic small bowel tissue
Subcutaneous panniculitis-like T-cell lymphoma
Presents with clinical features of panniculitis and also has striking inflammatory histologic features accompanying dispersed malignant cells in subcutaneous tissue
The neoplastic T/NK-cells in these lymphoma subtypes are large and frequently pleomorphic. They typically have cytotoxic features, with granules containing perforin, granzymes and TIA-1 contributing to their necrotizing/inflammatory behavior.
On histology, tumors are frequently found to have numerous histiocytes with apoptotic debris. Neoplastic cells have round to oval hyperchromatic nuclei with inconspicuous nucleoli and abundant pale cytoplasm
Hepatosplenic T-cell lymphoma
Rare lymphoma of the young, with a median age of onset of 30 years
Most present with hepatosplenomegaly, are pancytopenic at presentation, and half have circulating lymphoma cells (which portends poor prognosis).
Liver and spleen are diffusely enlarged by cord-like intrasinusoidal lymphoid cell infiltration (A), but no solid tumor. Histologic section shows erythroid and megakaryocytic hyperplasia with interstitial and intrasinusoidal neoplastic cells. The cells vary somewhat in size and morphology from patient to patient, but will have moderately abundant pale cytoplasm. In terminal-stage disease, they may transform into blast cells.
Immunophenotypically, they are CD2+ CD3+, CD56+, granzyme M+, and TIA-1+, but CD4/CD8 double negative, CD5-, perforin-, granzyme B-. (D) shows a CD3 staining to highlight the cells in the spleen.
If involvement is slight, IHC staining of sinusoidal endothelium for von Willebrand factor, CD31 or CD34 may be useful to highlight the location of infiltrating cells
Peripheral T-cell lymphoma, not otherwise specified
Accout for 6% of NHL, occur in a wide range of ages
There is usually extensive disease by presentation, with 65% of patients presenting in Stage IV. Extranodal involvement and B symptoms are more common than in B cell lymphomas. Bone marrow involvement is frequent. Prognosis is even worse than DLBCL.
Lymph node histology varries widely. Underlying architecture is usually preserved with the lymphoma replacing only part of the structure. Numerous reactive plasma cells, macrophages, eos, and lymphocytes are present and may obscure the neoplastic cells or give the impression of Hodgkin’s disease. Cytology is extremely broad, and even includes clear cell, immunoblasti, and Reed-Sternberg cytology. Even within one tumor, cytology may be pleomorphic. Almost universally, these are aggressive malignancies with frequent mitoses.
Immunophenotypically, loss of pan-T antigens CD5 and CD7 as well as CD4/CD8 double negativity is common. CD3 positivity is usually preserved. NK cell markers may be present (perforin, granzyme B, TIA-1).
Clonal TCR rearrangement is a vital part of diagnosis. Genetically, these lymphomas are heterogeneous, but many have complex karyotypes.
“Gray Zone” Lymphoma
Nickname for B-cell lymphoma, unclassifiable, features inbetween DLBCL and classical Hodgkin lymphoma
Looks like a lymphoma made out of many, closely packed Reed-Sternberg cells which stain CD15+ CD20+ CD30+
Diffuse-variant follicular lymphoma
Aggressive form of follicular lymphoma where the classic “tight clusters of germinal centers” architecture is lost in favor of diffuse sheets, sometimes with remnants of “poorly formed” GCs. Tend to occur in the groin.
These will universally express CD23 in addition to CD10.
Genetically, these tumors tend to lack Bcl2 rearrangements / t(14;18), but will often show del(1p36).
Subcapsular sinus
The sinus within the capsule of a lymph node. A small number of lymphocytes can generally be seen flowing within. If seen, this is a sign of good lymph node architecture.
