Case 2 -
B Cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL and Burkitt Lymphoma
Brigham and Women's Hospital
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This is a biopsy from a 64 yo female with had a history of new, intermittent abdominal pain. A CT scan showed a large (8 X 7 cm) retroperitoneal mass on the pancreas. Patient has a history of fibroids only.
White count = 7.5, normal differential Hematocrit = 41 Platelets = 331 LDH = 364 (normal range 135-214) No palpable andenopathy
Case 2 - Slide 1
Large lymphoid cells growing in a diffuse pattern with irregular nuclear contours, immature chromatin, prominent nucleoli.
The case presented was an example of the so-called "double- hit" lymphoma which harbors rearrangement
of both the cMYC and BCL2 loci. It is classified in the latest WHO as "B cell lymphoma, unclassifiable,
with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma".
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Histologically, the tumor cells are large in size with fine, almost blast-like chromatin, irregular
nuclear contours, variably prominent nucleoli, and a sheet-like growth pattern. In other examples, the
tumor cells may more closely resemble typical Burkitt lymphoma or DLBCL. Phenotypically, the tumor is
positive for markers of follicle center B cells (i.e. CD19+, CD10+, Bcl6+) and Bcl2. The tumor cells
showed dim CD20, as has been reported for "double hit" lymphomas. Genetically, FISH analyses using a
"split apart" probe set showed rearrangement of the cMYC locus, and using a "come together" probe set
showed fusion of the IgH and BCL2 loci.
The histologic and phenotypic pattern raises the following differential diagnoses: diffuse large B
cell lymphoma, Follicular lymphoma Grade 3B, Burkitt lymphoma, acute lymphoblastic lymphoma.
B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma.
Prior to obtaining the results of the genetic tests, this case was classified as "Diffuse large B cell
lymphoma". In this case, the rearrangement of BCL2 locus would have been expected given this tumor has
phenotypic evidence of follicle center cell origin (CD10+, BCL6+) and, in addition, expresses Bcl2
protein. Less expected was the rearrangement of cMYC. FISH for a cMYC rearrangement was prompted by the
immature or "blastic" chromatin pattern of the tumor cells. The same morphologic finding prompted IHC
for TDT (which was negative, ruling out a lymphoblastic lymphoma). Despite the presence of a cMYC
rearrangement, neither the morphology nor the immunophenotype support the diagnosis of Burkitt lymphoma.
Review of the Literature/Treatment Options (if applicable):
1. In papers comparing the molecular profiles of DLBCL and Burkitt lymphoma, a subset of cases
originally classified as either DLBCL or atypical Burkitt lymphoma showed gene expression profiles
intermediate between DLBCL and BL. Many of these cases had both cMYC and BCL2 rearrangements- so called
"double hits". A majority of these cases had cMYC rearrangements (like BL) in the context of an
underlying complex karyotype (like DLBCL). The clinical course for patients with tumors that were
"double hit" and/or cMYC in the context of a complex karyotype was uniformly poor.
2. Additional studies exploring outcome of patients with "double hit" lymphomas treated with R-CHOP
have showed dismal responses to this chemotherapeutic regimen. For the case presented here, the
patient's tumor grew straight through R-CHOP and RICE and died within 8 months of the diagnosis.
3. More recent data suggests that otherwise typical DLBCLs can harbor (unsuspected) cMYC
rearrangements in up to 10% of cases and that these tumors respond worse than those without a cMYC
rearrangement to conventional DLBCL therapy (R-CHOP).
In general, FISH for a cMYC rearrangement should be considered whenever there is/are: 1)
Transformation of a prior or underlying low grade follicular lymphoma to an aggressive large cell
lymphoma. 2) Morphologic and or immunophenotypic features that satisfy the diagnostic criteria of "B cell
lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma". 3) The
diagnosis of de novo large B cell lymphoma with phenotypic evidence of follicle center cell derivation
and BCL2 expression.
- A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling.
Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF, Bernd HW, Cogliatti SB, Dierlamm J, Feller AC, Hansmann ML, Haralambieva E, Harder L, Hasenclever D, Kühn M, Lenze D, Lichter P, Martin-Subero JI, Möller P, Müller-Hermelink HK, Ott G, Parwaresch RM, Pott C, Rosenwald A, Rosolowski M, Schwaenen C, Stürzenhofecker B, Szczepanowski M, Trautmann H, Wacker HH, Spang R, Loeffler M, Trümper L, Stein H, Siebert R; Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe.
N Engl J Med. 2006 Jun 8;354(23):2419-30. PMID:16760442
- Molecular diagnosis of Burkitt's lymphoma.
Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, Greiner TC, Weisenburger DD, Rosenwald A, Ott G, Müller-Hermelink HK, Gascoyne RD, Delabie J, Rimsza LM, Braziel RM, Grogan TM, Campo E, Jaffe ES, Dave BJ, Sanger W, Bast M, Vose JM, Armitage JO, Connors JM, Smeland EB, Kvaloy S, Holte H, Fisher RI, Miller TP, Montserrat E, Wilson WH, Bahl M, Zhao H, Yang L, Powell J, Simon R, Chan WC, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project.
N Engl J Med. 2006 Jun 8;354(23):2431-42. PMID:16760443
- MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy.
Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, Horsman DE, Gascoyne RD.
Blood. 2009 Oct 22;114(17):3533-7. Epub 2009 Aug 24. PMID:19704118
- B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma.
Snuderl M, Kolman OK, Chen YB, Hsu JJ, Ackerman AM, Dal Cin P, Ferry JA, Harris NL, Hasserjian RP, Zukerberg LR, Abramson JS, Hochberg EP, Lee H, Lee AI, Toomey CE, Sohani AR.
Am J Surg Pathol. 2010 Mar;34(3):327-40
- Characteristic expression patterns of TCL1, CD38, and CD44 identify aggressive lymphomas harboring a MYC translocation.
Rodig SJ, Vergilio JA, Shahsafaei A, Dorfman DM.
Am J Surg Pathol. 2008 Jan;32(1):113-22