The morphological features of follicular lymphoma presenting in the thyroid gland are not well characterised, leading to difficulties in its recognition by histopathologists and to uncertainties in patient management. In the present study, regardless of t(14;18)/IGH-BCL2
status, all 22 cases showed a destructive atypical lymphoid infiltrate which contained areas with, or was predominantly composed of, follicles showing typical morphological characteristics of follicular lymphoma. Recognition of these was aided by immunohistochemistry which showed a germinal centre phenotype (Bcl-6 +/- CD10 positive) together with immunophenotypic features supportive of malignancy (Bcl-2 expression, immunoglobulin light chain restriction, altered MIB1 staining, and/or loss of CD10 expression). However, many cases also contained an expansive extrafollicular neoplastic component. This feature was seen more frequently in the present series than in the large series of (predominantly nodal) follicular lymphomas that we have previously examined (4
), and has also been recognised in follicular lymphomas at other extranodal sites (23
). In most cases CD10 and/or Bcl-6 were expressed by the interfollicular B cells, but as in other follicular lymphomas (17
), these antigens were often downregulated and staining was sometimes negative. Importantly in all of the present cases, the interfollicular infiltrate formed readily identified, and often striking, lymphoepithelial lesions.
Appreciation of the above features afforded ready distinction from reactive infiltrates. Additional support was provided in many cases by molecular demonstration of clonal immunoglobulin gene rearrangement and/or by the detection of a chromosomal translocation involving BCL2
. Potentially more difficult is the distinction of follicular lymphoma in the thyroid gland from MALT lymphoma, particularly those cases showing prominent follicular colonisation (31
). Indeed, in this study, MALT lymphoma was the diagnosis or differential diagnosis in 13 of the 17 cases that were received as referrals for second opinion. In those study cases lacking t(14;18)/IGH-BCL2
, the presence of typical follicular lymphoma architecture in at least one area, the cytomorphology of the neoplastic cells, and the expression of CD10 and/or Bcl-6 in the neoplastic follicles and often in the extrafollicular component, confirmed the diagnosis of follicular lymphoma. A lack of CD10 staining (seen in four cases) is well recognised in follicular lymphomas showing grade 3 morphology or t(14;18)/IGH-BCL2
), while expression of Bcl-6, even in colonised follicles, is not expected in marginal zone lymphomas (16
). Additional features which were helpful in the differential diagnosis from MALT lymphoma include a lack of plasma cell differentiation, a lack of any reactive or partially infiltrated follicles, and weak or absent immunoglobulin heavy chain staining. The presence in some of our cases of features overlapping with MALT lymphomas is similar to reports of CD10+ Bcl-2+, t(14;18)+ follicular lymphomas mimicking MALT lymphomas in the stomach and lung (37
). Together these studies highlight that the presence of an expansive extrafollicular infiltrate forming lymphoepithelial lesions, even those with lumina expanded by lymphoid cells (coined “MALT ball” lymphoepithelial lesions (13
)), is not diagnostic of a MALT lymphoma.
MALT lymphoma and DLBCL of the thyroid gland arise in almost all cases from pre-existing chronic lymphocytic / Hashimoto thyroiditis, and patients with Hashimoto thyroiditis have a 60-80-fold increased risk of thyroid lymphoma (13
). By analogy to gastric MALT lymphoma, it is likely that MALT lymphoma of the thyroid gland arises from an auto-reactive post-germinal centre B cell in the context of immunological help from auto-reactive T cells (32
). It is therefore pertinent that evidence of chronic lymphocytic thyroiditis was present in 13 of our 22 cases of follicular lymphoma, suggesting that follicular lymphoma of the thyroid gland may also arise from the organised lymphoid tissue of thyroiditis. Since the clinical data available were, in some cases, incomplete, and thyroid tissue surrounding the lymphomas was not always available for review, the incidence of thyroiditis in our series may be underestimated. Examination of immunoglobulin heavy chain gene somatic mutation patterns has shown that follicular lymphoma arises from an antigen-selected germinal centre B cell, and has suggested that, at least early in the evolution of the lymphoma, antigen stimulation may provide an important stimulus for clonal expansion (6
). One study suggested that immunoglobulins derived from some follicular lymphomas may bind auto-antigens (15
). It is also clear that additional, perhaps non-cognate, signals from other cells in the germinal centre microenvironment can provide important stimuli to the neoplastic cells in at least a subset of follicular lymphomas (12
). It can be hypothesised, therefore, that follicular lymphoma of the thyroid gland may also be supported by (auto)antigen stimulation and/or by immunological stimuli generated in the context of thyroiditis.
The combined analysis of clinical, morphological, immunophenotypic and genetic data revealed the presence of two clearly distinct groups among our study cases. One group shared pathological features with typical adult follicular lymphoma: the presence of a t(14;18)/IGH-BCL2
, the expression of Bcl-2 and CD10, and a predominance of WHO grade 1-2 lymphomas (48
). These features are not only shared with the majority of primary nodal follicular lymphomas, but can also be seen in follicular lymphomas with characteristic clinicopathological features arising at some other extranodal sites including the gastro-intestinal tract (11
) and the ocular adnexa (18
), as well as in a proportion of primary follicular lymphomas of the skin (40
) and salivary gland (41
). For example, primary follicular lymphoma of the gastrointestinal tract has a predilection for duodenal involvement, is usually of low grade and CD10-positive, and typically expresses Bcl-2 as a result of a t(14;18)/IGH-BCL2
). Interestingly, all but one of the IGH-BCL2
and/or Bcl-2-positive cases in the present study presented with stage 2-4 disease. However, follicular lymphoma rarely involves the thyroid gland secondarily (44
) and several features suggest that at least the majority of these cases arose within the thyroid gland itself: in all cases the thyroid gland was the presenting and largest single site of disease; 5 cases had only stage 2 disease (small volume cervical lymph node involvement); and there was evidence of thyroiditis in five cases (including a history of autoimmune thyroiditis in a patient with stage 4 disease). Nevertheless, the possibility that this group includes some cases in which the thyroid gland is the site of presentation of disease originating in nearby lymph nodes cannot entirely be excluded.
The other group of cases lacked both IGH-BCL2
translocations and Bcl-2 expression, were often WHO grade 3, and included several CD10-negative cases. This latter constellation of features is thus similar to that of a heterogeneous minority of follicular lymphomas lacking IGH-BCL2
that has been recognised in several studies of follicular lymphomas arising at other sites (22
). Interestingly, although most such cases occur in lymph nodes, they may be over-represented at extranodal sites (23
). For example, in several studies of primary cutaneous follicular lymphoma, IGH-BCL2
was absent in 60-100% of cases, while Bcl-2 staining was negative in more than approximately 40% of cases (8
). We and others have identified similar features in follicular lymphomas of the testes of both adults and children, Kojima et al
found the majority of primary follicular lymphomas of the salivary gland to lack IGH-BCL2
, and Goodlad et al
reported similar findings in non-cutaneous extranodal follicular lymphomas from a range of sites (5
In contrast to the cases showing Bcl-2 expression and/or IGH-BCL2
, all of those lacking both these features remained localised to the thyroid gland (stage 1). This is in keeping with the results of other studies which suggest that IGH-BCL2
/Bcl-2-negative follicular lymphomas more often present with low stage disease than do typical follicular lymphomas (21
). The reason for this strict localisation is unclear, but it is possible that follicular lymphomas lacking Bcl-2 expression might remain dependent upon antigen or other stimuli within the thyroid microenvironment for survival, while the expression of Bcl-2 in other cases may allow lymphoma cells to survive in lymphoid tissue away from the thyroid gland. The question of primary site notwithstanding, the analysis of the Bcl-2 / IGH-BCL2
status of follicular lymphomas presenting in the thyroid gland is of potential clinical importance in distinguishing cases in which disease is likely to be localised from those in which there may be extra-glandular disease, as different treatment approaches may be appropriate in these two groups. Furthermore, this study suggests that the differences in biology and stage between the two groups identified may be reflected in differences in clinical outcome, although extended follow-up and study of additional cases are required before conclusions can be drawn.
In summary, follicular lymphoma of the thyroid gland includes cases with typical genetic and immunophenotypic features of follicular lymphoma, as well as a group lacking both Bcl-2 expression and IGH-BCL2 translocation and often having a higher grade morphology, in keeping with a recognised subset of follicular lymphomas over-represented at several other extranodal sites. These groups differ in their tendency to spread beyond the thyroid gland, but both show similar morphological features including frequent expansive extra-follicular infiltrates with prominent lymphoepithelial lesions which have previously been regarded as indicative of MALT lymphoma.