|
Hematopathology
|
Case 1 -
|
Case 1a: Follicular Lymphoma, Grade 1 (Of 3)
Case 1b: Langerhans Cell Sarcoma, Clonally Related to the Original Follicular Lymphoma, So-called "Transdifferentiation" of the Follicular Lymphoma Clone
Andrew L. Feldman
Mayo Clinic
Rochester, MN
|
Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:
under each thumbnail image below. You must have Aperio ImageScope installed on your PC.
|
If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy: | 
|
Or, click on slide thumbnail images to view each slide
in a Web-based slide viewer, which is somewhat slower.
If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.
Clinical History:
A 52 year-old male presented with lymphadenopathy in 2000 and underwent a right
inguinal lymph node biopsy (Case 1a). Bone marrow biopsy showed involvement by the same process seen in
the lymph node. The patient was treated with immunochemotherapy and had persistent, but stable, disease
for the next 8 years. In 2008, at age 61, his lymphadenopathy increased and he underwent a left inguinal
lymph node biopsy (Case 1b).
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Case 1a (2000
Biopsy): The right inguinal lymph node showed effacement of the nodal architecture by atypical,
back-to-back lymphoid follicles with thinned mantle zones. The atypical follicles extended beyond the
lymph node capsule into the surrounding fibroadipose tissue. At higher power, the follicles were
composed almost entirely of small cleaved cells (centrocytes). Larger centroblasts were rare (0-5/hpf).
Phenotype (flow cytometry): Positive: CD10, CD19, CD20, kappa light chain Negative: CD3, CD5, CD23,
lambda light chain Molecular studies: Not done at time of diagnosis.
Case 1b (2008 Biopsy): The left
inguinal lymph node showed marked infiltration by a population of medium to large atypical cells with
abundant cytoplasm. The cells formed nodules or small sheets, sometimes containing foci of necrosis. In
some areas a pronounced sinusoidal pattern of infiltration was noted. At higher power, many of the
atypical cells showed folded ("reniform") or multilobated nuclei. The background consisted mostly of
small, cytologically unremarkable lymphocytes with occasional, scattered eosinophils. Rare residual
follicular structures were identified; these had regressed, hyalinized centers.
Phenotype
(immunohistochemistry): Positive: CD1a, CD2, CD4, CD68, langerin, S100 Partial: BCL2 (focal, weak in
tumor; negative in residual follicle centers), CD19 (weak cytoplasmic), CD45 (focal, weak), PAX5
(partial, weak) Negative: CD3, CD5, CD8, CD10, CD20, CD30, CD43, CD79a, CD163, cytokeratins (AE1/AE3,
CAM5.2), EMA, HMB45, lysozyme, melan A, tyrosinase
Molecular studies: Immunoglobulin gene rearrangement
was performed in both the 2000 and 2008 biopsies, and showed clonal bands of the same size in both
specimens. Fluorescence in situ hybridization (FISH) was performed on the 2008 specimen using probes to
14q32(IGH) and 18q21 (BCL2) and showed IGH/BCL2 fusion in the large tumor nuclei. Combined
immunofluorescence/FISH was performed using the IGH and BCL2 probes and an antibody to langerin and
showed the cells with IGH/BCL2 fusion were positive for langerin.
Case 1 - Slide 1
|
Case 1 - Slide 2
|
Case 1a - Figure 1
H&E, 4x. A low power view of the lymph node from the 2000 biopsy shows numerous, back-to-back follicles with thinned mantle zones. |
Case 1a - Figure 2
H&E, 20x. At higher power, the follicles have a monotonous cellular composition and lack tingible body macrophages. |
Case 1a - Figure 3
H&E, 100x (oil). At high power, the cells within the follicles are mostly small cleaved cells (centrocytes). Occasional larger cells with oval nuclei containing watery chromatin likely represent follicular dendritic cells. |
Case 1b - Figure 1
H&E, 4x. A low power view of the lymph node from the 2008 biopsy shows nodules and small sheets of cells with focal necrosis. |
Case 1b - Figure 2
H&E, 10x. At slightly higher power, there is a distinct sinusoidal pattern to the infiltrate in this field. |
Case 1b - Figure 3
H&E, 20x. The atypical cells are medium to large in size, and have abundant cytoplasm. Foci of necrosis are present. |
Case 1b - Figure 4
H&E, 40x. In this field the sinusoidal pattern is appreciated. The largest of the atypical cells have folded or lobated nuclei. |
Case 1b - Figure 5
H&E, 100x (oil). In this high power view, the folded ("reniform") nuclei are easily appreciated. |
Differential Diagnoses:
Case 1a: Follicular lymphoma, grade 1-2 Follicular lymphoma, grade 3
Follicular hyperplasia
Case 1b: Metastatic carcinoma Metastatic melanoma Diffuse large B-cell lymphoma
Anaplastic large cell lymphoma Histiocytic sarcoma Langerhans cell sarcoma
Final Diagnosis:
Case 1a: Follicular lymphoma, grade 1 (of 3)
Case 1b: Langerhans cell sarcoma,
clonally related to the original follicular lymphoma, so-called "transdifferentiation" of the follicular
lymphoma clone
Case Discussion:
This unusual case is a striking example of lineage plasticity, in which a low grade
follicular lymphoma transformed (or "transdifferentiated") to Langerhans cell sarcoma after an 8 year
period of stable disease. The original follicular lymphoma (FL) was morphologically and phenotypically
characteristic, with the lymph node biopsy showing effacement of the architecture by back-to- back,
atypical follicles composed almost entirely of centrocytes (grade 1). A bone marrow biopsy showed
evidence of involvement, indicating stage IV disease. Complete clinical information is not available,
but the patient received immunochemotherapy including rituximab with cyclophosphamide, vincristine and
prednisone (R-CVP) and had persistent but stable disease for 8 years. He then presented with increasing
lymphadenopathy and another lymph node biopsy was performed. The 2008 biopsy showed a clearly malignant
population of cells extensively infiltrating the lymph node, with some areas showing a marked sinusoidal
pattern and other areas showing small sheets of cells with focal necrosis. Cytologically, many of the
cells had large pleomorphic nuclei that were often folded ("reniform") or multilobated. Architecturally,
the pattern of involvement raised the possibility of a metastatic solid tumor such as carcinoma or
melanoma, though there was no clinical evidence of a prior or synchronous primary lesion. Because of the
history of follicular lymphoma, transformation to diffuse large B-cell lymphoma also was considered,
though neither the architecture nor the cytology was typical for this entity. Among the lymphomas,
T-cell anaplastic large cell lymphoma (ALCL) could be considered, since this tumor often has a sinusoidal
pattern of lymph node involvement; furthermore, the lobated (and even some wreath-like) nuclei of the
tumor cells bear some resemblance to those seen in the "hallmark" cells of ALCL. ALCL has no known
relationship to FL, and, if diagnosed, would be considered an unrelated occurrence. A recent report [1]
described histiocytic and dendritic cell (H/DC) neoplasms in patients with FL (described in further
detail below), meriting consideration of this diagnosis in the present case. Though histiocytic tumors
typically demonstrate sheet-like growth, a sinusoidal distribution may be seen occasionally; in addition
the folded or lobated nuclei seen in the present case may be seen in tumors of histiocytic origin.
Langerhans cell sarcoma (LCS) is an aggressive, frankly malignant tumor of Langerhans cells which has not
been associated with FL previously. LCS often presents a diagnostic challenge. LCS is distinguished
from Langerhans cell histiocytosis (LCH), a disease of lower histologic grade though generally also
considered neoplastic. The tumor cells of LCH have characteristic folded or "grooved," bland nuclei, and
often are accompanied by numerous eosinophils. In contrast, LCS cells have pleomorphic nuclei which
often do not resemble those of LCH, typically have few or no accompanying eosinophils, and may not show
the classic immunophenotype of LCH (discussed below). In the present case, the tumor cells did have
folded nuclei, though distinct "grooves" were difficult to appreciate, and a sparse accompanying
infiltrate of eosinophils was present. As can be seen in the phenotyping results, and as is typical with
tumors of unclear lineage, an extensive battery of immunohistochemical stains was performed. An initial
panel performed elsewhere revealed that the tumor cells were strongly positive for S100, negative for
keratin, and showed focal weak positivity for CD45. The focal CD45 positivity is a helpful finding, but
is not always present; we have seen dendritic cell tumors with a sinusoidal pattern of distribution
misdiagnosed as metastatic melanoma based on S100 positivity. S100 may be positive in histiocytic
sarcomas, but the staining is usually weak or focal. Histiocytic sarcomas also typically express
lysozyme, which was absent in the present case. S100 expression is a consistent feature of dendritic
cell neoplasms. (Note: these are predominantly interdigitating dendritic cell sarcomas; follicular
dendritic cell sarcomas, despite the similarity in nomenclature, are considered to be of mesenchymal,
rather than hematopoietic, origin.) We routinely stain such tumors for CD1a and langerin to evaluate for
the possibility of Langerhans cell origin. CD1a is well known; langerin (CD207) is a newer marker which
may have more specificity (e.g. negative in so- called "indeterminate" dendritic cell tumor), and
correlates with the presence of Birbeck granules. This is a useful feature, as ultrastructural
examination now is performed rarely. Expression of CD68 and CD4 often is seen in tumors of histiocytic,
dendritic cell, and Langerhans cell origin, and does not help distinguish among them. The CD4 positivity
in such tumors should not be considered an indication of T-cell lineage. (However, the CD2 expression in
the current case is aberrant.) The strong staining for S100, CD1a, and langerin in this case support a
diagnosis of LCS. A peculiar feature of the LCS in this case is the weak positivity for the B-cell
markers PAX5 and cytoplasmic positivity for CD19, possibly related to the relationship to the patient's
FL (see below). The weak degree of expression of these markers is not sufficient for a diagnosis of
diffuse large B-cell lymphoma in light of the strong positivity for S100, CD1a, and langerin, and the
negativity for other B-cell markers including CD20 and CD79a. No consistent genetic findings have been
recognized in Langerhans cell neoplasms. The molecular studies in the present case were performed to
determine the relationship of the LCS to the patient's prior FL. The 2008 lymph node showed a clonal
immunoglobulin gene rearrangement, unexpected for a tumor of Langerhans cell origin. The clonal peak was
identical to that obtained from the 2000 FL specimen. "Contamination" of the 2008 specimen by residual
FL cells might yield similar molecular results; however, there was no morphologic or immunophenotypic
evidence of FL in the specimen. To address this issue more definitively, we performed FISH studies for
the t(14;18) translocation that is the hallmark of (most cases of) FL. Not only was this translocation
present, but simultaneous immunofluorescent staining with an antibody to langerin demonstrated
unequivocally that the t(14;18) was present in the langerin-positive cells. Taken together, these
molecular findings provide evidence that the patient's LCS derived from the original FL clone.
Review of the Literature/Treatment Options:
Early data on hematopoiesis suggested
that hematopoietic cells derive from pluripotent stem cells and develop in a unidirectional fashion into
lineage-committed mature cells. While this general schema remains accurate, the degree of "commitment"
to a given lineage has come into question: recent data suggest that mature hematopoietic cells have the
potential for significant lineage plasticity under the appropriate conditions. In murine studies, for
example, it was shown that mature B cells can be reprogrammed into mature macrophages by altering the
expression of lineage-associated transcription factors [2]. These reprogrammed cells demonstrated both
phenotypic and functional (e.g. phagocytosis) features characteristic of macrophages. This phenomenon
has been termed "transdifferentiation," i.e. conversion of one mature ("differentiated") phenotype into
another. (In some circumstances this may actually be a two-step process, consisting first of
"dedifferentiation" into a pluripotent precursor cell, followed by "redifferentiation" into a mature cell
of a different lineage [3].
) If this phenomenon can be demonstrated in mature B cells, does it occur in
neoplasms derived from this cell type? Several studies have suggested that patients with precursor
B-cell neoplasms (B lymphoblastic leukemia and lymphoma, B- ALL) can develop clonally related tumors of
histiocytic origin (i.e. analogous to macrophages)
[4,
5,
6,
7],
suggesting either the phenomenon of
transdifferentiation or the existence of a common precursor cell giving rise to both neoplasms. It could
be argued, however, that B-ALL is not a neoplasm of truly "mature" cells, and perhaps retains lineage
plasticity not seen in mature non-Hodgkin lymphomas. A recent study examined 8 patients with follicular
lymphoma (FL) and either synchronous or metachronous histiocytic or dendritic cell (H/DC)
neoplasms [1].
In all cases, the FL and H/DC tumors were found to be related by molecular studies (a combination of PCR,
DNA sequencing, and FISH), showing that even mature B-cell lymphomas can "transdifferentiate." As
suggested by the murine model mentioned above, the shift in lineage was accompanied by changes in
expression of lineage-associated transcription factors (PAX5, CEBP b , and PU.1). The present case is
another example of this phenomenon. While LCS has been reported to arise from precursor T lymphoblastic
leukemia/lymphoma [8], this case is thought to be the first example of transdifferentiation of FL to LCS.
Low-grade FL is an indolent, but currently incurable disease. About 30% of patients exhibit
transformation to a higher grade neoplasm at some point in their disease course, which typically is
associated with an aggressive clinical behavior leading to death. The majority of these are
transformations to diffuse large B-cell lymphoma, but transformations to high-grade B-cell lymphomas also
occur. Such transformation events have been associated with secondary genetic alterations, such MYC
translocation. "Transdifferentiation" of FL to histiocytic sarcoma, a dendritic cell tumor, or LCS
appears to represent another type of transformation event. Potential genetic events associated with this
type of transformation have not been identified, but might be related to the change in transcription
factor expression that accompanies the shift in lineage. It is not known what conditions might favor
transdifferentiation of FL rather than the more common transformation to a higher grade B-cell lymphoma.
Interestingly, recent work has suggested that "sporadic" HD/C tumors may have clonal immunoglobulin gene
rearrangements, despite the absence of a prior documented B- cell neoplasm [9]. This finding suggests
that lineage plasticity during (or prior to?) hematopoietic tumorigenesis may be even more common than
presently thought. Limited data are available regarding the treatment or outcome of
"transdifferentiated" FL. When they occur sporadically, most H/DC tumors and LCS are aggressive
malignancies with poor outcome. In addition, they are sufficiently rare that identifying optimal
treatment regimens is exceedingly difficult. In the present case, the patient's condition quickly
deteriorated at the time of the LCS diagnosis. He was not a candidate for further therapy and died 3
months later.
Conclusion(s):
Mature lymphocytes and their respective neoplasms have more plasticity than previously
thought. FL can "transdifferentiate" into clonally related histiocytic sarcomas, dendritic cell tumors,
or Langerhans cell sarcoma. This may be seen as a form of lymphoma transformation, though far less
common than transformation into diffuse large B-cell lymphoma or other B-lineage neoplasms. Awareness of
the phenomenon of transdifferentiation may help in the diagnosis and subclassification of unusual
neoplasms occurring in patients with a previous history of lymphoma.
References:
- Feldman, A.L., et al., Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood, 2008. 111(12): p. 5433-9.
- Xie, H., et al., Stepwise reprogramming of B cells into macrophages. Cell, 2004. 117(5): p. 663-76.
- Cobaleda, C., W. Jochum, and M. Busslinger, Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature, 2007. 449(7161): p. 473-7.
- Feldman, A.L., et al., Histiocytic sarcoma after acute lymphoblastic leukaemia: a common clonal origin. Lancet Oncol, 2004. 5(4): p. 248-50.
- McClure, R., et al., Clonal relationship between precursor B-cell acute lymphoblastic leukemia and histiocytic sarcoma: a case report and discussion in the context of similar cases. Leuk Res. 34(2): p. e71-3.
- Dictor, M., et al., Clonal evolution to histiocytic sarcoma with the BCR/ABL rearrangement 14 years after acute lymphoblastic leukemia. Leuk Lymphoma, 2009. 50(11): p. 1892-5.
- Costa da Cunha Castro, E., et al., Clinicopathologic Features of histiocytic lesions following ALL, with a review of the literature. Pediatr Dev Pathol, 2009: p. 1.
- Feldman, A.L., et al., Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans- cell histiocytosis. Lancet Oncology, 2005. 6(6): p. 435-437.
- Chen, W., et al., High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas. Am J Surg Pathol, 2009. 33(6): p. 863-73.
|
|
|
|
|
Click to view with ImageScope
Click to view with a Web-Based Viewer
