Hematopathology Diagnoses Too Easy to Miss!
Malignant Lymphomas Mimicking Reactive Processes
Marsha Kinney, James Cook and Steven Swerdlow
The WHO defines follicular lymphoma as a malignant neoplasm of follicular center cells (i.e.,
centrocytes and centroblasts) with a growth pattern that is at least partially follicular. 
Follicular lymphoma accounts for approximately 30% of all non-Hodgkin lymphomas in adults in the US, and
the incidence of this disorder has been increasing over recent years.
therefore represents the most commonly encountered type of small B-cell lymphoma in routine pathology
practice. As such, any pathologist who routinely evaluates lymph node or other extranodal biopsies for
possible lymphoproliferative disorders will frequently encounter the potential pitfalls associated with
follicular lymphoma. The three cases below were chosen to illustrate how some challenging cases of this
common entity may be misdiagnosed as a reactive process.
Follicular lymphoma (grade 1 of 3), confined to germinal
centers (i.e. "follicular lymphoma in situ")
The patient was a 66 year old man with a history of
persistent thrombocytopenia and mild splenomegaly. CT scans showed no evidence of lymphadenopathy, and a
bone marrow biopsy was unremarkable. The clinical impression was idiopathic thrombocytopenic purpura.
Due to failure to respond to medical management, a splenectomy was performed. At resection, the spleen
weighed 425 grams.
The histologic sections showed an intact architecture with
slightly prominent white pulp nodules that included prominent marginal zones. In focal areas, the
germinal centers appeared atypical with increased numbers of small cleaved cells.
Immunohistochemical stains showed the germinal centers to
be positive for CD10 and BCL6, and predominantly negative for BCL2. Very focally, clusters of intensely
BCL2 positive cells were present within the germinal centers. Flow cytometric studies showed numerous
polyclonal B-cells. However, gating on CD10 positive B-cells demonstrated kappa light chain restriction
(approximately 3% of total cells analyzed).
FISH studies for t(14;18)(q32;q21) (IGH/BCL2) were performed on intact paraffin sections. Analysis within the
atypical appearing germinal centers demonstrated numerous cells containing IGH/BCL2 fusion signals.
Follicular lymphoma, BCL2 protein negative.
The patient was a 43 year old woman with a history of
low grade follicular lymphoma, status post bone marrow transplant. Subsequently, the patient developed a
soft tissue mass lesion. A biopsy was performed and evaluated at an outside institution where a
diagnosis of "atypical follicular hyperplasia" was rendered. The case was received in consultation for
The histologic sections showed a lymphoid proliferation with
numerous germinal centers that appeared atypical without clear polarization. Residual but attenuated
mantle zones were present.
Flow cytometric studies showed surface immunoglobulin
negative B-cells. Immunohistochemical stains showed numerous CD20 positive, CD10 positive cells within
the germinal centers that were negative for BCL2.
PCR studies for a monoclonal immunoglobulin heavy chain
rearrangement were negative. However, FISH studies for t(14;18)(q32;q21) (IGH/BCL2) were positive.
Follicular lymphoma, with admixed reactive germinal centers.
The patient was a 43 year old woman with left axillary adenopathy. Biopsy
revealed a 4 cm lymph node.
The histologic sections show a proliferation of germinal centers, some of which were
polarized and contained tingible body macrophages, suggestive of reactive germinal centers. In other
areas, however, the germinal centers were atypical with increased small cleaved cells. Focal areas
contained reactive-appearing germinal centers with small clusters of small cleaved cells within them.
Immunohistochemical stains showed numerous CD20 positive
cells within the follicles and moderate numbers between follicles. A CD10 stain highlighted the germinal
centers. Areas with prominent small cleaved cells were more strongly positive than the reactive
appearing germinal centers. A BCL2 stain showed a mixture of positive and negative germinal centers.
Focally, some germinal centers were largely BCL2 negative, but contained clusters of intensely BCL2
positive small cleaved cells. Flow cytometric studies demonstrated a CD10 positive, surface
immunoglobulin light chain lambda restricted B-cell population.
FISH studies for t(14;18)(q32;q21) (IGH/BCL2) were
positive within the atypical germinal centers, and were negative in other germinal centers.
Difficult to Diagnose Follicular Lymphomas
The "typical" follicular lymphoma:
Fortunately, the diagnosis of
follicular lymphoma in most cases is relatively straightforward. Classic examples of follicular lymphoma
display several characteristics that assist in appropriate diagnosis and classification. These include:
Unfortunately, none of the findings described above are constant in follicular lymphoma, leading to
potential errors. In the following sections bellow, we discuss the ways in which atypical sites of
presentation, variant morphologic patterns, and unusual phenotypic findings may lead to misdiagnosis as a
- Clinical presentation: Nodal disease, usually high stage at
diagnosis (stage III-IV).
- Morphology: Nodular growth pattern, frequently with "back to
back" follicles. Malignant germinal centers are distinguished from reactive germinal centers by a more
homogeneous proliferation of centrocytes and centroblasts, lack of polarization, lack of tingible body
macrophages, and thinned to absent mantle zones.
- Phenotype: CD10 and BCL6 expression is generally present, and
monoclonal surface immunoglobulin is detectable by flow cytometry. Most cases coexpress BCL2 protein.
- Cytogenetics: Most cases contain a t(14;18)(q32;q21) involving
IGH and BCL2
Sites of Presentation:
Most patients with follicular lymphoma have
widespread nodal disease at the time of diagnosis, with only 20-30% of patients presenting with stage I
or II disease.
There is frequent involvement of the spleen
While extranodal involvement may occur, this is most frequently in the presence
of clinically apparent nodal disease. Initial presentation of a follicular lymphoma at a solitary
extranodal site is relatively uncommon.
Case 3 represents an example of a low grade follicular lymphoma presenting in the spleen. CT scans
performed prior to splenectomy had shown no evidence of adenopathy elsewhere, suggesting disease was
limited to the spleen. Due to this uncommon presentation, this diagnosis might not be considered in such
cases. However, studies suggest that follicular lymphoma presenting in the spleen may be more frequent
than commonly appreciated. For example, in a study of 42 patients where a small B-cell lymphoma was
initially diagnosed by splenectomy, 12 cases were follicular lymphomas, compared to 13 cases of splenic
marginal zone lymphoma.  This finding demonstrates that when splenectomy is formed with a
concern for a possible lymphoproliferative disorder, the possibility of follicular lymphoma should be
Follicular lymphomas may also present at other extranodal sites, with each setting producing a
distinct differential diagnosis. In most cases, these lymphomas resemble their systemic nodal
counterparts, and the largest source of diagnostic error is probably a simple failure to adequately
consider the possibility of follicular lymphoma in the differential diagnosis. Notable sites include
each of the following:
1) Skin: There is a vast, albeit often conflicting and confusing,
literature regarding primary cutaneous follicular lymphomas. The current approach to these cases is
described in the WHO/EORTC classification of cutaneous lymphoproliferative disorders  which
will be discussed in the context of another case.
2) GI Tract: Follicular lymphomas presenting in the GI tract present a
special challenge to pathologists, as these cases may be mistaken for either reactive processes or for
other non-Hodgkin lymphomas.
These cases may have an increased incidence in the
duodenum, as compared to other parts of the GI tract.  While some cases present as large
transmural mass lesions, others may present as mucosal polyps that may simulate reactive lymphoid
aggregates. Some patients will show multiple mucosal lesions, a type of presentation termed
"lymphomatous polyposis" and most frequently encountered as a form of GI involvement by mantle cell
lymphoma. The differential diagnosis in general also includes an extranodal marginal zone lymphoma (MALT
3) Others: Follicular lymphomas have been described with primary
presentation in many other locations including the orbit, the female GI tract, and thyroid among
Variations in Histologic Pattern:
Several histologic variants of
follicular lymphoma exist, and a complete description of such findings is beyond the scope of this
discussion. However, the cases presented above do directly relate to two such variants: so-called
"follicular lymphoma in situ" and follicular lymphoma with admixed reactive germinal centers. Each of
these is discussed separately below.
"Follicular lymphoma in situ"/Intrafollicular Neoplasia:
In most cases of follicular lymphoma, the neoplastic germinal center cells proliferate not only within,
but also between the follicles. Indeed, the presence of a proliferation cells with a germinal center
cell phenotype (i.e. CD10 positive, BCL6 positive) infiltrating between follicles strongly suggests the
presence of a lymphoma of germinal center origin. In some cases of follicular lymphoma, however, the
interfollicular component is either minimal or is absent entirely, and the overall architecture is
preserved. Case 3, for example, is an example of a follicular lymphoma that appears to be localized
completely to the germinal centers. Such cases have been previously described as "in situ localization
of follicular lymphoma" or "follicular lymphoma in situ." This terminology has now been incorporated
into the revised 2008 WHO classification (intrafollicular neoplasia/"in situ" follicular
Cong et al reported a series of 23 cases of in situ localization of follicular lymphoma. 
These cases were defined by the presence of preserved architecture with focal atypical germinal centers
that were positive for BCL2 by immunohistochemistry. In most cases, the BCL2 positive germinal centers
represented only a minority of the follicles present, and numerous reactive-appearing, BCL2 negative
germinal centers were also present. In routine H&E stains, the corresponding germinal centers were
recognized as atypical due to an increased number of small lymphocytes. Prior to evaluation by
immunohistochemistry, a diagnosis of "atypical follicular hyperplasia" had been considered in most of
The true biologic significance of "follicular lymphoma in situ" has yet to be determined. It remains
unclear whether all such cases represent true malignant neoplasms, or whether these cases could possibly
represent a "pre-malignant" change that has not yet progressed to an overt lymphoma. Interestingly, in
animal models, it appears that the presence of an IGH/BCL2 translocation
alone is insufficient to produce an overt malignancy, suggesting other genetic "hits" may be necessary
for complete lymphomagenesis.  In addition, sensitive PCR studies have shown that IGH/BCL2 transcripts can be detected in the peripheral blood of up to one-quarter
of healthy individuals.
Could cases of "follicular lymphoma in situ" represents
patients who have developed an IGH/BCL2 translocation, leading to BCL2
positive germinal centers, but still lack other abnormalities needed for development of an overt
lymphoma? Of the 23 cases of "in situ localization of follicular lymphoma" reported by Cong et
al,  5 patients had concurrent specimens from other sites with an overt follicular lymphoma.
Of the additional 13 cases with follow up information, 3 more developed an overt follicular lymphoma
within 1-6 years later. The remaining patients showed no other evidence of disease with a median
followup of 15.5 months. In case 3, the patient has displayed no evidence of lymphoma 3.5 years after
splenectomy. Additional studies with long followup periods will be necessary to determine if such
patients will inevitably progress to a clinically overt lymphoma.
Follicular lymphoma with admixed reactive germinal centers:
Another challenging histologic pattern was reported by Su et al, who described 5 cases
of follicular lymphoma that displayed areas with infiltration of reactive germinal centers by the
neoplastic follicular lymphoma cells.  These cases are distinct from "follicular lymphoma in
situ" where the overall architecture is intact. Rather, these cases display effacement of the overall
architecture by numerous follicles, including some reactive-appearing forms, some overtly neoplastic
forms, and some that appear to be mostly reactive with clusters of follicular lymphoma within them. This
latter pattern of infiltration closely resembles the so-called "follicular colonization" of reactive
germinal centers seen in some cases of marginal zone lymphoma.  It has been suggested that
the neoplastic cells in follicular lymphoma may express adhesion molecules that result in localization to
benign germinal centers, possibly providing a mechanism of follicular colonization.
Case 5 is an excellent example of this phenomenon, showing focal involvement of reactive-appearing
germinal centers by a low grade follicular lymphoma.
A recent study has demonstrated that cases of follicular lymphoma with admixed reactive germinal
centers are frequently low stage at presentation.  This finding suggests that this
phenomenon may represent an "early" form of follicular lymphoma. Additional studies will be required to
clarify the clinical significance of this histologic pattern.
Lymph node biopsies displaying either in situ localization of follicular lymphoma or admixed benign
germinal centers may be very difficult diagnose. In both of these conditions, the diagnosis could be
missed entirely if the lesion is not well sampled (i.e. in needle biopsy specimens). In any biopsy found
to contain prominent germinal centers, careful morphologic evaluation is obviously warranted to exclude
to the presence of focal disease. Atypical appearing areas should be investigated further by
immunohistochemical and/or genotypic studies.
Reactive Hyperplasia vs. Follicular Lymphoma: Immunophenotypic Studies:
The expression of CD10 and BCL6 may be readily evaluated in
paraffin embedded material using immunohistochemistry, and CD10 expression can also be routinely detected
by flow cytometry. Both benign and malignant germinal centers are expected to be positive for both CD10
and BCL6. As previously mentioned, the demonstration of CD10 positive or BCL6 positive cells
infiltrating between germinal centers is very suggestive of a neoplastic process.
It should be remembered, however, that a "follicular center cell phenotype" is not unique to
follicular lymphoma. CD10 expression is also found in many diffuse large B-cell lymphomas, Burkitt
lymphomas, lymphoblastic lymphomas of both precursor B-cell and precursor T-cell type, and even some
mature peripheral T-cell lymphomas.
BCL6 protein is even be more broadly expressed in a
wide variety of non-Hodgkin lymphomas, often due to translocations involving the BCL6 gene which may arise as secondary changes in many entities. 
Likewise, CD10 and BCL6 expression is not a constant feature of follicular lymphoma. In relatively
recent studies using either sensitive flow cytometric analysis or modern, robust commercial monoclonal
antibodies, CD10 expression is generally found in 90-100% of grade 1 and grade 2 follicular
CD10 expression is clearly less common in cases of grade 3 follicular
lymphoma, with a reported incidence ranging from 51-70%.
Interestingly, lack of CD10
expression may be particularly associated with cases showing a grade 3B morphology (those lacking admixed
centrocytes).  It should be noted that expression of CD10 may be down-regulated in the
inter-follicular component of the lymphoma, such that immunohistochemical stains may detect CD10 only
within the germinal centers in some cases.
In CD10 negative cases, demonstration of BCL6
expression by immunohistochemistry, although not specific, may support a germinal center cell
origin.  BCL6 expression, however, also appears to be less frequent in cases with grade 3
The demonstration of BCL2 expression by germinal center B-cells (CD10 positive, BCL6 positive)
provides strong evidence of a lymphoma of germinal center cell origin. Immunostains for BCL2 are
therefore extremely useful in the distinction between follicular hyperplasia and follicular lymphoma. In
such cases, the BCL2 stain should be correlated with a stain for CD3 or another T-cell marker, as any
T-cells residing within the germinal center are also expected to be BCL-2 positive. Flow cytometric
studies may also be useful to detect BCL2 expression in CD10 positive B-cells.  BCL2
expression is seen in >90% of cases of grade 1-2 follicular lymphoma, but only 50-76% of grade 3
Cases with a grade 3B morphology are particularly likely to be BCL2
While the demonstration of BCL2 expression assists in establishing a
diagnosis of follicular lymphoma, one clearly must be prepared to diagnose BCL2 negative follicular
lymphomas as well. Case 4 represents an example of a follicular lymphoma lacking detectable BCL2
One of the primary advantages of flow cytometric studies as opposed to immunohistochemistry in
paraffin sections is the ability to analyze surface immunoglobulin light chain expression. While most
cases of follicular lymphoma will display detectable light chain restriction, some cases will be
essentially surface immunoglobulin negative, as seen in Case 4. Although some investigators have
suggested that the presence of a large population of surface immunoglobulin negative B-cells may be taken
as presumptive evidence of a neoplastic process,  some cases of florid follicular hyperplasia
also have sizable surface immunoglobulin negative B-cell populations.  One should therefore
interpret such results with a degree of caution, and correlate the findings with a thorough morphologic
and further phenotypic characterization. In some cases, permeabilization to allow detection of
cytoplasmic immunoglobulin expression may be helpful.
Reactive Hyperplasia vs. Follicular Lymphoma: Cytogenetic Studies:
The t(14;18)(q32;q21) involving IGH and BCL2 is the cytogenetic hallmark of follicular
lymphoma.  The demonstration of an IGH/BCL2 translocation in a small B-cell lymphoma by
classical cytogenetics or by FISH strongly suggests the diagnosis of follicular lymphoma. FISH studies
performed on intact paraffin sections may be especially useful in cases with only focal
disease,  as illustrated in Case 3. It should be remembered, however, that the IGH/BCL2
translocation is also present in a subset of diffuse large B-cell lymphoma, and has been rarely reported
in other lymphoproliferative disorders such as chronic lymphocytic leukemia.
cytogenetic studies are best interpreted in the context of other morphologic and immunophenotypic
As with the expression of CD10 and BCL2 protein, the incidence of the IGH/BCL2 translocation varies with the grade of the follicular lymphoma. The
translocation is present in >90% of grade 1-2 cases, but in only 30-50% of cases with a grade 3
Cases of grade 3B appear to be especially unlikely to carry a
Follicular lymphomas lacking an IGH/BCL2 translocation are
morphologically, phenotypically, and cytogenetically heterogeneous. Some cases that lack an IGH/BCL2 translocation may nonetheless express BCL2 protein, due to polysomy of
the BCL2 locus or amplification of BCL2.
Fortunately, such alternate abnormalities will also be
detectable by FISH testing for IGH/BCL2. The demonstration of any of these
abnormalities would assist in differentiating follicular lymphoma from reactive follicular hyperplasia.
Other cases lack any detectable abnormality of the BCL2 gene and are
negative for BCL2 protein. Many of the cases lacking t(14;18), especially the grade 3 follicular
lymphomas, will contain a t(3;14)(q27;q32) involving BCL6 and IGH.
Conventional cytogenetic or FISH studies confirming a
BCL6 translocation may therefore also be helpful.
Lastly, it should be noted that while most cases of follicular lymphoma containing a t(14;18) will be
BCL2 positive for immunohistochemistry, this is not always the case, as illustrated in Case 5. In some
patients, mutations in the BCL2 gene may be acquired that render BCL2
protein undetectable with routinely employed antibodies,  or BCL2 protein expression may be
lost entirely. FISH testing for IGH/BCL2 may therefore be helpful in cases
where a diagnosis of follicular lymphoma is strongly suspected, even if a BCL2 immunostain appears
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