Case 2 -
Diffuse Large B-Cell Lymphoma, consistent with Mediastinal (Thymic) Large B-Cell Lymphoma
Massachusetts General Hospital
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The patient was a 33-year-old attorney who presented initially with mild dyspnea, possibly in
association with a cold. His symptoms resolved, but a few weeks later he noted an unusual sensation,
described as a tightening or tingling, in his right chest on deep inspiration. He also had low-grade
fever but no weight loss or convincing night sweats. He had a history of infectious mononucleosis during
high school, but his past medical history was otherwise unremarkable.
Radiographic evaluation revealed a 6 x 8 cm mediastinal mass. Biopsies of the mass were performed.
Case 2 - Slide 1
Case 2 - Figure 1 - There is a dense, diffuse infiltrate of atypical lymphoid cells, with a mottled light and dark pattern at low power.
Case 2 - Figure 2 - There is a dense, diffuse infiltrate of atypical lymphoid cells, with a mottled light and dark pattern at low power.
Case 2 - Figure 3 - The infiltrate is associated with sclerosis.
Case 2 - Figure 4 - In some areas there are scattered cells resembling lacunar cells scattered in a background of reactive cells.
Case 2 - Figure 5 - A few eosinophils are present.
Case 2 - Figure 6 - High power shows large atypical cells, including cells resembling lacunar cells and one binucleated Reed-Sternberg-like cell, with admixed small lymphocytes.
Case 2 - Figure 7 - Low power in this area shows a more uniform infiltrate of atypical cells.
Case 2 - Figure 8 - In these images, most atypical cells have large, round to oval nuclei, vesicular chromatin, prominent nucleoli and moderately abundant pale cytoplasm, and there are fewer admixed reactive cells than in figures 4 and 6.
Case 2 - Figure 9 - In these images, most atypical cells have large, round to oval nuclei, vesicular chromatin, prominent nucleoli and moderately abundant pale cytoplasm, and there are fewer admixed reactive cells than in figures 4 and 6.
Microscopic examination revealed a dense, diffuse infiltrate of large atypical lymphoid cells
associated in areas with sclerosis that ranged from fine to coarse. In areas, the infiltrate was
relatively monotonous, being composed of large lymphoid cells with round to oval, occasionally indented
nuclei with prominent nucleoli and moderately abundant pale eosinophilic cytoplasm, with few admixed
reactive cells. In other areas, some of the large atypical cells had the morphology of lacunar cells,
and there were infrequent binucleate cells resembling Reed-Sternberg cells. These areas also tended to
have a more substantial admixture of reactive cells, including occasional eosinophils. The microscopic
features were considered borderline between classical Hodgkin's lymphoma and diffuse large B-cell
lymphoma (mediastinal large B-cell lymphoma in this site).
Flow cytometric analysis showed 20% polytypic B cells, and T cells with CD4:CD8 ratio of 1:1; no
abnormal population was detected. Despite the heterogeneous microscopic features, the
immunohistochemical findings were uniform from one area to another. The large atypical cells were CD45+,
CD20+, CD79a+, Oct2+, Bob1+, MUM1+, bcl6+, CD10-, CD15-, EBV-LMP-. A few cells were CD30+. A few cells
were bright CD23+, while most were CD23-. Scattered small T cells (CD3+) were present.
Cytogenetic Analysis Showed an Abnormal Karyotype:
48XY, add(21)(q22), +mar1x2 /46,XY .
The microscopic features were considered borderline between classical Hodgkin's lymphoma and diffuse
large B-cell lymphoma (mediastinal large B-cell lymphoma in this site), and raised the question of a
"gray-zone lymphoma". However, the immunophenotype strongly favored B-cell lymphoma, and did not support
Hodgkin's lymphoma, and taken together the findings supported a diagnosis of diffuse large B-cell
Diffuse Large B-Cell Lymphoma, consistent with Mediastinal (Thymic) Large B-Cell Lymphoma
Staging revealed localized disease. The patient was treated with CHOP chemotherapy; his symptoms
resolved, but at completion of therapy he had a residual gallium-avid mass in the mediastinum. He was
then treated with a salvage regimen (ICE) and attained a complete remission. At last follow-up (5 years
after presentation), he describes feeling completely normal, and is training for a triathlon.
Mediastinal (Thymic) Large B-cell Lymphoma:
Mediastinal large B-cell lymphoma was first recognized as an entity distinct from mediastinal
lymphoblastic lymphoma.  Because of its characteristic clinical and pathologic features, it
has been included as a separate entity in both the REAL  and the subsequent WHO
It accounts for 2.4% of non-Hodgkin's lymphomas. 
Mediastinal large B-cell lymphoma mainly affects individuals between 20 and 50 years of
age,  with a median age that is in the thirties or early forties in many
There is a slight female preponderance.
Almost all patients have
symptoms related to the presence of a mediastinal mass, including dyspnea, chest pain, cough, superior
vena cava syndrome, or a combination of these. B symptoms (fever, sweats, weight loss) are found in
fewer than half of patients.
Clinical and radiographic evaluation reveals an anterior superior mediastinal mass that is described
as bulky (> 10 cm in greatest dimension) in approximately 75% of cases.
often surrounds and invades adjacent structures such as pleura, pericardium, lung, mediastinal soft
tissue, blood vessels and mediastinal lymph nodes. This lymphoma may involve the supraclavicular fossa
(lymph nodes or soft tissue), and occasionally, even the soft tissue of the chest wall or the sternum by
Lymphoma invading lung may penetrate bronchi and produce an
endobronchial mass. 
In the vast majority of cases, the lymphoma is confined to the thoracic cavity at presentation.
When disease is more widespread it tends to involve extranodal sites such as kidney, adrenal,
central nervous system and others. Marrow involvement is uncommon, occurring in no more than 5% of
Microscopic examination reveals a diffuse infiltrate of atypical lymphoid cells that is almost always
associated with sclerosis. The sclerosis can be band-like, can be intercellular, or can surround nests
of cells, in a compartmentalizing pattern.  Small and large foci of necrosis are common.
Vascular invasion, mainly affecting larger blood vessels, is also common. The classic cellular
composition includes a population of large cells with irregular, lobated nuclei and clear cytoplasm,
accounting for some or all of the neoplastic cells. However, the cytologic features do vary from case to
case, although they are usually uniform within a case.  Neoplastic cells may also be
centroblasts with round nuclei. A few cases are composed of anaplastic cells. In some cases, there is
an admixture of immunoblasts or Reed-Sternberg-like cells.
In a few cases, neoplastic
cells are relatively small, and have been described as small centroblasts;  when they have
clear cytoplasm, they may resemble monocytoid B cells.  There is a variable admixture of
small lymphocytes and histiocytes, and a few neutrophils may be present but plasma cells and eosinophils
are typically absent. In some cases thymic remnants can be identified; an immunostain for cytokeratin
can help to highlight these structures.
The neoplastic cells are diffusely positive for CD45 and for pan B-cell markers such as CD19, CD20,
CD22 and CD79a. The majority of cases (at least 70%) lack surface immunoglobulin (sIg); cytoplasmic
immunoglobulin (cIg) expression is rare. An interesting feature is that despite the lack of Ig in most
cases, CD79a, the sIg co-receptor, is typically present. Tumor cells also express Oct2 and Bob1,
transcription factors associated with immunoglobulin expression, so that the lack of these factors is not
the cause of absence of Ig.
Expression of CD30 is common, but staining is usually
weaker and more variable than in classical Hodgkin's lymphoma.
The majority of cases are
some cases are bcl2+.
CD10 is typically not expressed,
although in one series nearly one-third of cases were CD10-positive. 
T-cell-associated antigens, including CD5, are absent. 
CD21 is absent.
was expressed by tumor cells in 70% of the cases in one series.  There is no evidence of
Epstein-Barr virus infection of tumor cells. 
Some immunophenotypic features provide clues to the pathogenesis of this lymphoma, and also help to
set it apart as an entity distinct from other diffuse large B-cell lymphomas. In the majority of cases
neoplastic cells express MAL, a protein normally found only in T cells. MAL localizes to the
detergent-insoluble, glycolipid-enriched membrane domains involved in signal transduction and thus may be
involved in lymphomagenesis.  Other diffuse large B-cell lymphomas have been negative for
The expression pattern of a variety of factors in pathways associated with activation and cell
survival has been identified that is characteristic of mediastinal large B-cell lymphoma. cREL
(reticuloendotheliosis viral oncogene homologue), a member of the NF kB family of transcription factors,
is a subunit of the NFkB (nuclear factor k B) heterodimer found in the cytoplasm, bound to IkB (inhibitor
of NF kB) in its inactive state; upon activation, cREL is released and moves into the
Nuclear cREL protein is reported in 65% of mediastinal large B-cell lymphoma;
it may be expressed in other diffuse large B-cell lymphomas but it is less common (18% in one
report).  TRAF1, an NF kB target gene, is much more often expressed in mediastinal large
B-cell lymphoma than in other large B-cell lymphomas. Approximately half of mediastinal large B-cell
lymphomas express both nuclear cREL and cytoplasmic TRAF1; among non-Hodgkin's lymphomas, this
combination is highly specific for this type of lymphoma and is only rarely found in other diffuse large
B-cell lymphomas.  This pattern of immunostaining provides strong evidence for activation of
the NF kB pathway in many cases of this type of lymphoma, and supports the importance of NFkB in its
In its activated, phosphorylated form, STAT6 (signal transducer and activator of transcription 6)
dimerizes and enters the nucleus where it plays a role in regulating transcription, and mediating IL-4
(interleukin 4)/IL-13 transcriptional effects, such as cellular proliferation. Phosphorylated STAT6 is
found in the nucleus in most cases of mediastinal large B-cell lymphoma and only rarely found in other
diffuse large B-cell lymphomas. 
Genetic and Cytogenetic Features
Mediastinal large B-cell lymphomas have clonally rearranged Ig heavy and light chain genes. Even
though most cases lack Ig protein expression, analysis at the genetic level reveals Ig genes that appear
potentially functional. The Ig genes show a high load of somatic mutations, with evidence of isotype
switch, but without ongoing somatic mutation.  A few cases have had missense point mutations
There is no bcl2 rearrangement. Rare cases with bcl6 rearrangement have
been described. 
Mediastinal large B-cell lymphoma has characteristic cytogenetic features distinct from those of other
non-Hodgkin's lymphoma. Gains of chromosomal material are much more common than losses. The most common
areas showing gains include regions of chromosome 2, 9p, 12q and Xq. A small minority of cases show
high-level amplification of the proto-oncogene cREL.
cREL amplification does not, however, appear to correlate with increased NF
kB activity, and activation of NF kB appears to be independent of cREL
Gene profiling studies
have also shown features characteristic of mediastinal
large B-cell lymphoma. While the profile of mediastinal large B-cell lymphoma is again different from
that of other diffuse large B-cell lymphomas, it shows substantial overlap with that of classical
These and other studies suggest constitutive activation of the
JAK/STAT pathway and of the NF kB pathway,
which are probably important in the
pathogenesis of this lymphoma. Elevated levels of NFkB support cell survival via promotion of
antiapoptotic TNFa signaling. There are elevated levels of IL13Ra (which phosphorylates JAK2 and STAT1),
as well as of JAK2 and STAT1, compared to other diffuse large B-cell lymphomas. 
FIG1, upregulation of which is induced by IL4; multiple other gene products from
cytokine pathways; TNF (tumor necrosis factor) family members; and extracellular matrix components are
also present at increased levels.
Mediastinal large B-cell lymphoma also shows a
decrease in IgM and other members of the B-cell receptor (BCR) signaling cascade.
Mutations in SOCS-1 (suppressor of cytokine signaling-1) may play a role
in activation of the JAK/STAT pathway. SOCS-1 is involved in regulation of
cellular proliferation, survival and apoptosis via JAK/STAT signaling. SOCS-1 downregulates the Janus kinases and provides negative feedback for STAT
activity. Mutations and deletions of SOCS-1, which have been described in
mediastinal large B-cell lymphoma, may lead to delayed degradation of JAK2, and may contribute to
persistent activation of JAK/STAT.
Cell of Origin
Thymic B cell (asteroid cell)
Treatment and Outcome
Patients are typically treated with combination chemotherapy with or without radiation therapy. The
chemotherapy used has usually been either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
or more intensive third generation chemotherapeutic regimens such as MACOP-B (methotrexate, doxorubicin,
cyclophophamide, vincristine, prednisone, bleomycin) or VACOP-B (methotrexate, doxorubicin,
cyclophophamide, vincristine, prednisone, bleomycin).
High dose chemotherapy combined
with autologous stem cell transplant or autologous bone marrow transplant has been used in a small
proportion of cases.
Outcome has varied somewhat among different series, but in one
large study published in 2006, 77% of patients achieved complete remission, 12% achieved a partial
remission, and the 5-year overall survival was 75%.  When relapse occurs, it is usually
within one year of completion of chemotherapy, and almost always within two years. Patients may develop
relapses that are intrathoracic, extrathoracic or both.  Extrathoracic relapses tend to
involve unusual sites, such as kidneys, adrenal glands, gastrointestinal tract, central nervous system,
ovaries, breasts and other extranodal sites, although lymph nodes may be involved as well.
The sites of involvement and the strong tendency for relapses to occur only within a short
interval after treatment are additional features distinct from other diffuse large B-cell
A poor prognosis has been associated with older age, male sex, bulky disease, poor performance status,
higher stage disease, pleural effusion and pericardial effusion.
features, including cell size, sclerosis and necrosis, have no influence on prognosis.
Failure to respond to initial therapy is associated with a poor prognosis, as is the occurrence of
relapse; in either scenario, patients almost always succumb to lymphoma within a year.
Other Diffuse Large B-Cell Lymphomas
Mediastinal large B-cell lymphoma has characteristic histologic features, but they are not specific,
and it may be difficult to distinguish primary mediastinal large B-cell lymphoma from other large cell
lymphomas involving the mediastinum. Compared to other diffuse large B-cell lymphomas, mediastinal large
B-cell lymphoma is more likely to affect younger individuals and females, and to present with bulky
Mediastinal large B-cell lymphoma also is much more likely to attain a large
size within the thoracic cavity before dissemination. Mediastinal large B-cell lymphomas are more likely
to spread to unusual extranodal sites when they do disseminate, as noted above. They also have
distinctive immunohistochemical, cytogenetic and genetic features. Gene expression profiling studies
suggest that a few cases otherwise compatible with mediastinal large B-cell lymphoma have a molecular
signature that is distinct from other cases in this category, and more like that of other diffuse large
B-cell lymphomas, so that they may not represent true examples of mediastinal large B-cell
lymphomas.  As methods improve, criteria for the diagnosis of this disease will likely be
Classical Hodgkin's Lymphoma
Classical Hodgkin's lymphoma, particularly of nodular sclerosis type, shares many features with
mediastinal large B-cell lymphoma. Both lymphomas tend to affect younger adults, with some female
preponderance, and to produce mediastinal neoplasms that are characterized by a prominent sclerosis.
Hodgkin's lymphoma usually arises in lymph nodes but in the mediastinum, approximately half of cases
involve the thymus, and nearly one-quarter are confined to the thymus at presentation, so that a subset
of cases clearly arises in the thymus.  The cell of origin is a B cell for both lymphomas.
Mediastinal large B-cell lymphoma is composed of large atypical cells, some of which may resemble
Reed-Sternberg cells, that usually lack immunoglobulin and that may express CD30. In addition, the two
lymphomas have similar cytogenetic abnormalities, including frequent gains in 2p13-p16 and 9p24 (location
of REL and JAK2,
The gene expression profile of mediastinal large B-cell lymphoma is more like that of classical Hodgkin's
lymphoma than like that of other diffuse large B-cell lymphomas.
Like mediastinal large
B-cell lymphoma, the neoplastic cells of Hodgkin's lymphoma show evidence of activation of the NF kB
pathway as evidenced by nuclear cREL and bright cytoplasmic TRAF1 expression in most cases. 
Both may also have mutations in SOCS-1 which may play a role in their
pathogenesis . Rare cases of synchronous and metachronous lymphomas with one component
consisting of mediastinal large B-cell lymphoma and a second component consisting of classical Hodgkin's
lymphoma have been described.  These observations have led to the idea that mediastinal
large B-cell lymphoma and nodular sclerosis Hodgkin's lymphoma are closely related entities, possibly
sharing a common cell of origin and a common or similar pathogenesis.
With so many similarities, it is not surprising that in occasional cases it may be difficult to
distinguish mediastinal large B-cell lymphoma from mediastinal nodular sclerosis Hodgkin's lymphoma. In
favor of Hodgkin's lymphoma are an admixture of many reactive cells, especially eosinophils, neoplastic
cells with an appearance convincing for Reed-Sternberg cells and variants, CD15 expression by tumor
cells, diffuse bright CD30 expression by tumor cells, absence or weak, variable expression of B-cell
antigens (CD20, CD79a) on tumor cells and absence of CD45 on tumor cells. Patients with mediastinal
Hodgkin's lymphoma also seem to present with less severe symptoms related to the presence of a mass than
those with mediastinal large B-cell lymphoma.
Mediastinal Gray-Zone Lymphoma
This term has been used to describe lymphomas with features intermediate between those of mediastinal
large B-cell lymphoma and classical Hodgkin's lymphoma, in which subclassification is
difficult.  Examples of gray-zone lymphomas include a lymphoma with morphology consistent
with mediastinal large B-cell lymphoma, but with an immunophenotype more like that of Hodgkin's lymphoma,
or, conversely, a lymphoma with the morphology of classical Hodgkin's lymphoma but with diffuse, strong
Thymic epithelial neoplasms, particularly well-differentiated thymic carcinoma (WHO type B3), may
mimic mediastinal large B-cell lymphoma on routinely stained sections. Cohesive growth, nested tumor
cells and perivascular spaces favor thymoma. Immunophenotyping shows cytokeratin expression by the
neoplastic cells, and often, an admixture of immature T cells (CD1a+, TdT+).
Extragonadal germ cell tumors with pathologic features of seminoma are known as germinomas. A
significant subset of these rare neoplasms presents as localized mediastinal masses. The ages of
patients affected overlaps with mediastinal large B-cell lymphoma, but germinoma is seen virtually
exclusively in males. It has an excellent prognosis. 
Microscopic examination reveals nests or sheets of large polygonal cells with large oval nuclei that
are often flattened along one edge, prominent nucleoli and abundant pale, glycogen-rich cytoplasm. The
tumor is accompanied by a variably prominent lymphoid stroma, often with lymphoid follicles and
epithelioid granulomas. The histologic features are distinctive, but there may be some overlap with the
morphology of mediastinal large B-cell lymphoma, and definite diagnosis may be difficult on a small
biopsy. Immunophenotyping and special stains can establish a diagnosis, as the neoplastic germ cells are
PLAP+, Oct4+, and negative for lymphoid markers, with cytoplasm that is PAS+.
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