Which choice does NOT belong in the differential diagnosis?

Germ cell tumor

Lymphoma (wrong) <- your answer

Sarcoma

Thymic tumor

All of the above belong in the differential diagnosis (the correct answer)

The question above accounts for 20 % of your total score for this case.

Superior vena cava (SVC) is occluded.

True (wrong) <- your answer

False (the correct answer)

The question above accounts for 20 % of your total score for this case.

Mass is mostly necrotic.

True

False (correct!)

The question above accounts for 20 % of your total score for this case.

There is evidence of pericardial involvement.

True (correct!)

False

Coronal image demonstrates a moderate pericardial effusion.

Which of the following is the MOST LIKELY diagnosis?

Germ cell tumor (wrong) <- your answer

Lymphoma (the correct answer)

Sarcoma

Thymic tumor

None of the above

Statistically speaking, with a huge solid anterior mediastinal mass in a

young person, lymphoma of some variety is most likely. That is what this
turned out to be.
Findings
Large soft-tissue anterior mediastinal mass with significant
neovascularity
Substantial posterior mass effect on mediastinal structures with
some vascular attenuation
Pericardial and left pleural effusion
Differential diagnosis

 Lymphoma
Germ cell tumor/teraroma
Thymoma/thymic carcinoma
Thyroid tumor
Sarcoma
Diagnosis: Large B-cell lymphoma of mediastinum
Young man with chest tightness, dysnpea, fever, nausea
Page 4 of 4
Key points
Diffuse large B-cell lymphoma (DLBCL) is a fast-growing,
aggressive form of non-Hodgkin's lymphoma (NHL).
There are more than 20 types of NHL. DLBCL is the most
common type, making up about 30% of all lymphomas.
Diffuse large B-cell lymphoma can be fatal if left untreated,
but with timely and appropriate treatment, up to half of all
patients are curable.
This subtype of DLBCL within the chest cavity usually
involves the thymus.
Primary mediastinal large B-cell lymphoma comprises 7% of
all diffuse large B-cell lymphomas and accounts for 2.4% of
all non-Hodgkin's lymphomas. If this subtype of diffuse large
B-cell lymphoma recurs, it can cause problems with other
organs, including the liver, gastrointestinal tract, kidneys,
ovaries, and central nervous system.
The five-year survival rate of patients with DLBCL is between
26% and 73%.
Reference

Smith SM. Mediastinal lymphoma. Medscape

website.http://www.emedicine.com/med/topic1366.htm. Updated
July 22, 2013. Accessed April 29, 2015.

Primary mediastinal B-cell lymphoma (PMBCL) is a diffuse large B-cell nonHodgkin lymphoma that arises in the thymus. PMBCL affects young adults in their
third to fourth decade of life and has a slight female predominance. It accounts for
5-7% of all aggressive lymphomas and 2-3% of all non-Hodgkin lymphomas.
PMBCL was initially recognized in the Revised European-American Classification
of Lymphoid Neoplasms (REAL) as a subtype of diffuse large B-cell lymphoma
(DLBCL) that involves the mediastinum. However, PMBCL became a fully
recognized separate entity in 2001 when the World Health organization (WHO)
identified that PMBCL represents a distinct clinicopathologic disease and should be
classified as such.
Gene expression studies have confirmed that PMBCL is molecularly different from
DLBCL and that it may resemble Hodgkin lymphoma.[1, 2, 3] Because of its skewed

age distribution, PMBCL accounts for a much higher proportion of lymphomas in

patients who have undergone autologous hematopoietic stem cell transplantation
(auto-HSCT). Importantly, the majority of patients are cured with modern intensive
combination chemoimmunotherapy that is often followed by either involved-field
radiation or auto-HSCT. In fact, in some retrospective studies, PMBCL was shown
to even have better prognosis than DLBCL when all other variables were equal. [4,
5]
Important to note, however, is that the role of radiotherapy (XRT) and/or autoHSCT is being challenged in the current modern era of highly sophisticated
imaging modalities such as positron emission tomography (PET) scanning. See the
image below.

Example of mediastinal
lymphoma at diagnosis. A large tumor mass is present in the anterior mediastinum, and an
associated pleural effusion can also be seen.

While PMBCL is generally limited to the mediastinum, hematogenous and

extranodal involvements are common in relapsed patients, who have generally a
poor prognosis.[6, 7]
For more information, see B-Cell Lymphoma.

Several studies have explored the underlying genetic and molecular features that
lead to the evolution of primary mediastinal B-cell lymphoma (PMBCL). Gene
expression profiling has clearly demonstrated that this disease entity is different
from diffuse large B-cell lymphoma (DLBCL) and has identified several deregulated
pathways involved in the pathogenesis of PMBCL. Steidl and Gascoyne eloquently
summarized the recurrent gene alterations involved in the pathogenesis of PMBCL.
[8]

Gene expression profiling has demonstrated overexpression of genes encoding the

NF-kappa-B pathway, suggesting its involvement in the pathogenesis of PMBCL.

Further, inhibiting I-kappa-B, which activates NF-kappa-B signaling, was shown to

induce cell kill in vitro in PMBCL cell-lines.
Chromosomal gains and amplifications of the REL gene locus on band 2p16.1
have been found in 50% of cases.[8, 9, 10] Other chromosomal aberrations that affect
NF-kappa-B pathways include BCL-10 (1p22) and MALT-1 (18q21).
Song et al identified a tumor suppressor gene that encodes the A-20 protein, which
acts as an inhibitor to the NF-kappa-B pathway downstream from the tumor
necrosis factor (TNF) receptor.[11] Mutations in that gene have been found in over
30% of PMBCL cases, but it has also been described in other lymphoid
malignancies.[12, 13] Another mutated tumor suppressor gene is SOCS1(suppressor
of cytokine signaling). SOCS1 usually acts as an inhibitor to the JAK-STAT6
pathway, preventing continued activation and proliferation. [14] In fact, Mottok et al
suggested that SOCS1 deletion mutations were present in 45% of 20 studied
patients.[15]
More recent studies have also shown a role of immune deregulation in PMBCL
pathogenesis. Specifically, the reduced expression of major histocompatibility II
complex genes led to decreased infiltrating cytotoxic T-cells, and some
investigators have suggested this can lead to inferior outcomes, arguing that more
studies exploring the role of immune escape in PMBCL are warranted. Another
mechanism by which PMBCL cells escape immune surveillance has been by
overexpressing certain surface molecules such as PD-1 ligands and receptors,
which, in turn, leads to inactivating infiltrating effector T cells.

History
Primary mediastinal B-cell lymphoma (PMBCL) patients usually present with a bulky anterior mediastinal mass in
their third or fourth decade in life. Superior vena cava (SVC) syndrome is common, and, in some reports, 50-80% of
patients can have some form of SVC compromise. Phrenic nerve palsy, dysphagia, hoarseness, and breast swelling
(in women) can occur. Shortness of breath can be due to pleural effusion, massive mediastinal mass, pericardial
effusion, or airway compression. Systemic symptoms (fever, weight loss, night sweats) occur in 30-47% of patients.
Most patients have localized symptoms that depend on the bulk and extent of the disease; however, if recurrence
develops, a hematogenous pattern of spread to parenchymal organs, such as the liver, kidneys, or brain, is common.
Symptoms in recurrent disease accordingly vary and depend on the organ involved.

Physical examination
Physical examination may reveal the following:

SVC syndrome, with congestion of face and upper extremities and occasional airway compromise
Palpable mass in the supraclavicular area
Dullness at the lung bases

Respiratory distress, especially with direct extension to the lungs

Peripheral adenopathy (unusual except in the supraclavicular area)
Performance status should be noted because this is an important prognostic indicator.[16]

Additional findings
Laboratory studies are not diagnostic of PMBL, but over 70% of patients can have elevated lactate dehydrogenase
(LDH) levels. By definition, patients do not have bone marrow involvement, and 75-80% of patients are usually
staged as having stage I or II disease. Most patients present with bulky disease defined as a mass greater than 10
cm in largest diameter.

Differential Diagnosis
The differential diagnosis of primary mediastinal B-cell lymphoma (PMBCL) includes the following:

Acute Lymphoblastic Leukemia

Germ Cell Tumors
Hodgkin Disease
Lymphoblastic Lymphoma
Malignant Anaplastic (Ki 1+) Lymphoma
Thymoma

Diagnostic considerations
Differentiating PMBCL from other malignancies that involve the mediastinum is extremely important because the
diagnosis affects management and outcome.[17]Similarly important is differentiating PMBCL from systemic diffuse
large B-cell lymphoma (DLBCL) with mediastinal involvement. This latter entity often affects older patients and usually
has involvement of distant lymph nodes (away from the mediastinum) and for some, bone marrow is affected with
disease.
Distinguishing Hodgkin lymphoma from PMBCL can be challenging. Both diseases can affect younger adults and
both entities can be similar histologically. Flow cytometry studies can be helpful, as many patients with classic
Hodgkin lymphoma have neoplastic cells that express CD15 and CD30, while they lack expression of B-cell markers.
As mentioned above, PMBCL patients express B-cell markers and have weak CD30 expression.
Despite significant advances, few cases continue to be difficult to diagnose and some patients have features similar
to classic Hodgkin lymphoma and PMBCL at the same time. These patients are described as having "Gray zone
lymphoma" or "B-cell lymphoma with features intermediate between DLBCL and classic Hodgkin lymphoma."
Management of these patients is not well defined, but most authorities treat these individuals similar to DLBCL
treatment programs.

Workup
Laboratory studies
Perform a CBC count with differential and platelets. Perform an electrolyte panel and liver function tests.
Elevation in the serum lactic dehydrogenase (LDH) or beta-2 microglobulin level value is an adverse prognostic
feature and usually is seen in the majority of patients.

The markers alpha-fetoprotein and beta-human chorionic gonadotropin (beta-HCG) are often highly elevated in
patients with mediastinal germ cell tumors, constituting an important differential diagnosis in males.

Imaging studies
Obtain a chest radiograph (posteroanterior, lateral). A mass larger than one third the diameter of the thorax is
considered bulky and indicates a poor prognosis. This might have therapeutic implications later in treatment if
radiotherapy (XRT) is being considered.
Obtain CT scans (chest, abdomen, pelvis). Extension to the pleura, pericardium, and even the chest wall is common.
Invasion of the liver, kidneys, and peripheral lymph nodes is more common at the time of recurrence. On occasion,
obtaining a CT scan of the neck and soft tissues might be warranted.
Positron emission tomography (PET) scans are considered standard of care procedure before initiating therapy. PET
scans are expected to become negative upon completion of successful treatment. Additional diagnostic or treatment
considerations (as discussed below) are suggested if the PET scans remain positive after completion of therapy.
Treatment decisions based solely on PET scan results are not encouraged, and patients might need to undergo
additional diagnostic procedures to confirm whether the PET scan findings are truly positive.
Consider other imaging studies if they are clinically indicated (eg, head CT scan or MRI, if the patient has neurologic
problems; see image below). Consider performing a multiple-gated acquisition (MUGA) scan to assess cardiac
function before anthracycline-based chemotherapy.

Isolated CNS relapse of primary mediastinal Bcell lymphoma.

Diagnostic procedures
Adequate diagnostic biopsy is needed and may require surgery to obtain a sufficient sample for accurate diagnosis.
Not uncommon, biopsies can initially be nondiagnostic owing to extensive fibrosis and necrosis, and additional
studies might be needed. Most commonly, patients either undergo mediastinoscopy or thoracoscopy depending on
the location and feasibility.[18]
Ancillary studies, which include immunohistochemistry, immunophenotyping (flow cytometry), and gene
rearrangement studies, are often necessary to establish the diagnosis.

Bone marrow aspirate and biopsy are necessary for staging. A unilateral sample is sufficient if the biopsy specimen is
larger than 2 cm. By definition, the bone marrow is not usually involved. Patients with marrow involvement might have
systemic diffuse large B-cell lymphoma (DLBCL) with secondary mediastinal disease, as opposed to primary
mediastinal B-cell lymphoma (PMBCL).
Other tests should be performed if clinically indicated (eg, thoracentesis for pleural effusion, lumbar puncture for
neurologic symptoms).

Treatment & Management

For patients who present with superior vena cava (SVC) syndrome, establishing the diagnosis in a timely and efficient
manner is critical. The authors advocate against initiation of radiotherapy (XRT) in these patients, and, rather,
recommend starting systemic chemoimmunotherapy. Radiation can alter the pathologic findings and would impair
accurate diagnosis; thus, it should be avoided except in extreme circumstances. Patients who are relatively stable
should undergo emergent diagnostic evaluation (as summarized above) followed by treatment initiation.

Chemoimmunotherapy
Combination anthracycline-based chemotherapy is the mainstay of treatment for primary mediastinal B-cell
lymphoma (PMBCL). The standard front-line regimen in the United States
is cyclophosphamide, doxorubicin (Adriamycin), vincristine, andprednisone combined with rituximab (CHOP-R).
Rituximab is a chimeric monoclonal anti-CD20 antibody that has transformed how B-cell lymphomas are treated and
has become a standard component of treating all B-cell lymphoma histologies that express CD20. However, a few
studies, mainly from Europe, have advocated themethotrexate, doxorubicin (Adriamycin), cyclophosphamide,
vincristine (Oncovin), prednisone, and bleomycin (MACOP-B) regimen, combined with rituximab.[19, 20, 21] The standard
CHOP-R regimen is now being challenged by a combination program that contains etoposide (dose-adjusted
EPOCH) plus rituximab (DA-EPOCH-R), although prospective randomized trials to accurately compare these 2
programs (CHOP-R vs DA-EPOCH-R) have not been completed.[22]
As PMBCL was recognized only recently as being a distinct entity, original studies that have established CHOP-R as
a standard therapy in diffuse large B-cell lymphoma (DLBCL) did not include PMBCL patients. Accordingly, the
German Lymphoma Study Group sought to confirm the impact of chemoimmunotherapy specifically on the PMBCL
subset of patients who were enrolled on their MiNT trial (MabThera (Rituximab) International Trial). [23]
In this trial, patients were younger than 60 years with DLBCL and had 0-1 risk factors according to the age-adjusted
International Prognostic Index (aaIPI). Patients were randomly assigned to 6 cycles of CHOP-like regimens with or
without rituximab. Consolidating XRT was given to sites of primary bulky disease. Of 824 patients enrolled, 87 had
PMBCL. Rituximab increased the rates of complete remission (unconfirmed) in PMBCL (from 54% to 80%; P =.015).
In PMBCL, rituximab virtually eliminated progressive disease (2.5% vs 24%; P =.006).With a median observation time
of 62 months for PMBCL, the 5-year event-free survival was improved (79.1% vs 47.3%; P =.011). Furthermore, 5year progression-free survival was improved by rituximab (89.8% vs 60.1%; P =.006). These data further confirmed
that the addition of rituximab to 6 cycles of CHOP-likechemotherapy improved long-term outcome for young patients
with PMBCL.
Patients should be evaluated clinically and radiographically to assure continued response. Interim positron emission
tomography (PET) scan evaluation is discussed separately below. Patients usually undergo 6 cycles of CHOP-R
administered every 3-weeks. The regimen has expected adverse effects and toxicities as discussed below, and the
use of growth factors (filgrastim or peg-filgrastim) is dependent on the patient's age and comorbidities. Given the
relatively younger age at PMBCL presentation, the authors advocate against the routine use of growth factors as
primary prophylaxis. Secondary prophylaxis, however, is recommended to ensure adequate dose density and
intensity.

Consolidation therapy and interim PET scans

Prior to the wide use and adaptability to PET scans, most patients underwent consolidative XRT or high-dose
chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) after completion of systemic
therapy. While this approach continues to be commonly used, it has become increasingly controversial, especially in
patients who attain complete PET scan negativity upon completion of systemic chemoimmunotherapy.
Several reports have suggested inferior survival in patients with DLBCL who have residual PET scan positivity at the
end of chemotherapy and other studies have shown that patients who have a positive interim PET scan (after 2-4
cycles of therapy) predict higher risk of subsequent relapse. [24, 25, 26] However, treatment decisions in patients who
remain PET positive after completion of systemic therapy should never be based solely on the PET scan
interpretation. Moskowitz et al showed in a large phase II study that the majority of DLBCL patients who remained
PET positive had no residual disease when diagnostic biopsies were performed.[27]In that report, 30% of the 98
enrolled patients had PMBCL.
Whether XRT should be delivered to all patients with PMBCL regardless of PET scan results or whether this
approach should be individualized based on PET and/or other clinical or prognostic features remain unknown.
Savage et al reported on the British Columbia experience. [28] CHOP-R followed by consolidative XRT was the adapted
approach to all PMBCL patients diagnosed and treated from 20012005. After 2005, PET scanning was used to
guide XRT following 6 cycles of CHOP-R. To that end, if the PET scan was negative, patients were observed and if
the PET scan was positive, consolidative XRT was given. In total, 176 patients were identified: 96 received CHOP-R
and 80 received CHOP. For the CHOP-R treated patients, 46 were treated in the XRT era with 80% receiving XRT;
50 were treated in the PET era; 38% received XRT. Comparing between eras, no overall survival was suggested by
adding XRT. Further, when PET-positive patients received XRT consolidation, no significant difference in outcome
was observed between PET-positive and PET-negative patients, suggesting that some patients can avoid undergoing
XRT when PET is used to guide therapy.
In an attempt to eliminate XRT, Dunleavy et al recently reported a phase II trial on 51 patients who were treated with
DA-EPOCH-R and showed excellent results. With a median follow-up of 5 years, event-free survival was 93% and
overall survival was 97%. For patients who had a PET on this study, the negative predictive value was 100%, while
the positive predictive value was 17%. This finding is in line with the data from Moskowitz et al (see above), for which
patients have false-positive PET scans after completion of therapy, and underscores the importance of not making
therapeutic decisions based on PET findings only. In all, only 2 patients (4%) underwent XRT when DA-EPOCH-R
was used.
The use of consolidative auto-HSCT in patients with PMBCL stems from the effectiveness of this approach in patients
with relapsed DLBCL.[29] Residual disease radiographically was hypothesized to represent persistent lymphoma and
patients underwent the aggressive salvage therapy as PET scans were not available then. With the advent of PET
and continued standardization of its interpretation, the authors recommend against routine use of auto-HSCT as a
primary consolidative approach. Whether patients who have residual disease that is established histologically should
undergo XRT or auto-HSCT is unknown. The authors favor enrolling these patients in clinical trials if available.
Outside of clinical trials, the decision needs to be individualized and would factor prognostic features, morbid
conditions, and patients' wishes. In general, the authors favor XRT and reserve auto-HSCT to patients who
subsequently relapse.

Relapsed disease
Patients with relapsed disease often have systemic involvement and many also have extranodal disease. These
patients are recommended to undergo salvage systemic chemotherapy followed by stem cell collection and
subsequent transplantation. The authors favor rituximab, ifosfamide, carboplatin, and etoposide (RICE) as a salvage
approach, although other regimens are acceptable. Patients who demonstrate chemosensitive disease (improvement
radiographically and on PET) are taken to transplantation. Patients who have refractory disease should be offered
clinical trials, although some can be considered for allogeneic bone marrow transplantation.

Treatment in pregnancy
Some patients are young women who may be pregnant at the time of diagnosis. The management of malignancy
during pregnancy raises specific and complex issues. Concern for the patient's health needs to be balanced with the
potential teratogenicity of the chemotherapy and the radiation administered for diagnostic examinations or as part of
treatment.
Termination of pregnancy is often recommended if the diagnosis is made in the first trimester. However, this is not
acceptable to all patients. In cases in which pregnancy is continued, the administration of chemotherapy drugs
without undue teratogenicity is often possible. Staging and restaging examinations are minimized. Radiography is
avoided, and MRI or ultrasonography procedures are used instead.
The administration of corticosteroids may exacerbate problems such as preeclampsia or glucose intolerance. Close
collaboration with an obstetrician is required.

Consultations
Patients should be referred to a medical hematologist or oncologist for treatment.

Follow-up
The vast majority of patients can be successfully treated in an outpatient setting for front-line care.
After completion of treatment, patients are usually seen in the outpatient clinic at regular intervals of 2-3 months for
the first year. Patients are seen every 3-4 months until 5 years. The authors recommend seeing patients annually
after that indefinitely. Routine surveillance CT scans and/or PET scans are not recommended after establishing
complete remission. The authors consider performing CT scans on some patients upon their request, especially if
they have high likelihood of relapse.

Complications
The chemotherapeutic drugs used for the management of lymphoma have numerous adverse effects. Nausea and
vomiting are common but can be avoided with the use of appropriate antiemetics. Hair loss occurs in most patients
but is completely reversible after the completion of treatment.
Mild peripheral neuropathy due to chemotherapy is common. Patients experience numbness in fingertips and toes.
Motor neuropathy is unusual.
Myelosuppression (bone marrow suppression) and moderate pancytopenia occur after every treatment cycle. Blood
counts typically reach their nadir approximately 10 days after the completion of a treatment cycle. Fatigue is common.
Neutropenic fever and infection are common complications of chemotherapy and require immediate treatment.
Approximately 10-20% of patients develop excessive neutropenia or an infectious complication. Primary prophylaxis
with antibiotics is not recommended, although it is used for some patients. The use of growth factors is discussed
above.
Cardiac toxicity due to chemotherapy is unusual but can occur. Cardiac toxicity from anthracyclines is dose
dependent and rare in the typical young patient with PMBCL. Serial monitoring with echocardiograms or multiplegated acquisition (MUGA) scans may be necessary in individual cases. Typically, patients undergo a MUGA scan to
evaluate the left ventricular ejection fraction prior to the initiation of chemotherapy. A MUGA scan is performed in most
centers only if clinical concerns arise about cardiomyopathy. Patients should not receive more than 400 mg/m 2 of
doxorubicin in their lifetime. The incidence of cardiomyopathy if this dose is exceeded is 7-8%. The use of

cardioprotectant agents may allow the administration of higher doses of anthracyclines, but these cardioprotectant
agents might affect the efficacy of chemotherapy. Therefore, cardioprotectant agents are not routinely recommended.
Rituximab is generally safe. It can cause fever and chills, particularly during the first administration. Rare cases of
anaphylactic reactions have been reported. Cases of hepatitis B virus (HBV) reactivation that have resulted in
fulminant hepatitis and death have been reported. Persons at high risk of HBV infection should be screened before
the initiation of rituximab. Carriers of HBV should be closely monitored for clinical and laboratory signs of active HBV
infection and hepatitis during and up to several months after rituximab therapy. All patients should have their hepatitis
titers checked before rituximab initiation.
Acute adverse effects of radiation are usually limited and include erythema of the skin and, sometimes, radiation
pneumonitis.
Late adverse effects related to treatment include decreased fertility, a slightly increased incidence of secondary
cancers in radiation fields (especially breast cancer among women treated during adolescence), and a slightly
increased risk for secondary leukemia, especially among patients treated with combined-modality therapy (ie,
chemotherapy and radiation).
In addition, coronary artery disease may be more common and may have an earlier onset if substantial areas of the
heart are exposed to radiation. Smoking and alcohol abuse should be avoided because of their association with
cancer and heart disease.

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