Staging

The Natural Thyroid Diet

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The recommended staging system is Musshoff's modification ofthe Ann Arbor staging system (36). See Table 1. Over 90% of patients present as stages IE or IIE.

PATHOLOGY Gross pathology

Enlargement of the thyroid gland, either rapidly or slowly, is the commonest gross manifestation (Figure 1). This is often accompanied by extrathyroidal extension into surrounding soft tissue and skeletal muscle. The lymphomatous gland varies in its naked eye appearance: fleshy, tan, white, grey or red with a fish-flesh appearance, firm or soft, multinodular, lobulated or with diffuse deposits, solid or cystic. The cut surface may be smooth, bulging or lobular. Foci of hemorrhage and necrosis may be present imparting a mottled or variegated appearance to the cut surface. Lymphomatous involvement of the gland ranges from 0.5 to 19.5 cm (36). Uninvolved thyroid tissue, if present, may show the macroscopic features of the associated lymphocytic thyroiditis: beige in color with fibrosis and lobular accentuation. Obviously, none of these gross features are specific to lymphoma of the thyroid gland.

LIGHT MICROSCOPY MZBL of MALT type

This type of lymphoma is probably the most histologically distinct and recognizable of all the primary thyroid lymphomas. The constituent cells are slightly larger than cen-trocytes and are called "centrocyte-like" cells in view of this resemblance. These cells have condensed chromatin, slightly irregular nuclear contours but are rarely, if ever, cleaved (Figure 2). The centrocyte-like cells have a propensity for permeating thyroid follicle epithelial cells giving rise to the histological hallmark of MALT lymphomas,

Figure 1. Gross illustration of a thyroid gland infiltrated by a lymphoma: enlarged, fleshy gland that is tan coloured.

the so-called "lymphoepithelial lesion" (Figures 3 & 4). Not only are the centrocyte-like cells seen insinuating between thyroid follicle cells but they are also found in between thyroid follicles within the stroma. The thyroid follicles bearing lymphoep-ithelial lesions vary in appearance from being relatively intact (Figure 5) to showing marked atrophy and destruction (Figure 6). In the more severe lymphoepithelial lesions, the follicles are markedly attenuated and may not be seen on H&E sections. Tombstones or the occasional residual epithelial cell may only be visible with a cytokeratin stain as a remnant of a previous follicle (Figure 5). Sometimes the centrocyte-like cells traverse the thyroid follicle cells and come to occupy the centres of the follicles dis-placing/kern-1ptreplacing the colloid, so-called "stuffed follicles" or what Derringer and colleagues have dubbed, "MALT balls" (36) (Figure 7). Other cellular components that are present in MZBL of MALT type include: plasma cells, mature, round, slightly elongated or lymphoplasmacytoid lymphocytes, monocytoid B-lymphocytes and cen-troblastic appearing cells (Figure 8). Indeed, the occasional eosinophil and histiocyte

Figure 2. Centrocyte-like cells are the dominant cell type in MZBL of MALT-type. They are slightly larger than mature centrocytes and have a slightly irregular, but not cleaved, nuclear contour.

may also be present. The infiltrate between thyroid follicles is typically heterogenous and the centrocyte-like cells almost exclusively participate and form lymphoepithelial lesions. However, plasma cells can form a major component of the infiltrate and can in some instances be the dominant cell type. The plasma cells are mainly mature in morphology although bi-nucleate forms and those harboring Russell and Dutcher bodies have been encountered. The plasma cells rarely, if ever, permeate the thyroid follicle epithelium and tend to have a para-follicular distribution (Figure 9). This may be so marked in some instances that there almost appears to be a "compartmentalization" of the plasma cells away from the centrocyte-like cells and they appear as a separate infiltrate. In general, they are admixed together. The monocytoid B-cell component, made up of uniform small to intermediate cells with characteristic abundant eosinophilic to clear cytoplasm, occurs in clusters of varying size. Centroblastic cells, larger cells with vesicular chromatin and prominent nucleoli, are found scattered in amongst the other cellular constituents (Figure 10). They are not the dominant cell type nor do they form cohesive aggregates in MZBL of MALT type.

Reactive lymphoid follicles are also a common feature in this type of lymphoma (Figure 11). These are found within the neoplastic infiltrate and are not related to the associated lymphocytic thyroiditis. The follicles warrant careful examination to separate

Figure 3. The centrocytes-like cells home into the thyroid follicles, traverse the epithelial cells and form lymphoepithelial lesions.
Figure 4. Under higher magnification, the centrocyte-like insinuate between and through the thyroid follicle cells with resultant disruption and destruction of the follicle.
Figure 5. A cytokeratin stain highlights a relatively intact follicle that nonetheless is permeated by centrocyte-like cells, some of which are present within the follicle lumen.
Figure 6. More destructive lymphoepithelial lesions with only remnants of thyroid follicle left. A cytokeratin stain is useful in showing residual epithelial cells within the dense lymphoid infiltrate.
Figure 7. So-called "MALT ball" or "stuffed follicle" where the neoplastic cells reside within the lumen of the thyroid follicle.

truly reactive germinal centers from so-called "follicular colonization". In this phenomenon the centrocyte-like cells home into the germinal centers oflymphoid follicles both in the thyroid gland and draining lymph nodes. The centrocyte-like cells displace the usual cells of the germinal center and this often imparts a nodular or follicular appearance to the neoplastic infiltrate. Morphologically the possibility of follicular lymphoma needs to be separated from a MZBL of MALT type with follicular colonization.

MZBL OF MALT TYPE WITH LARGE CELL TRANSFORMATION (MIXED MZBL AND DIFFUSE LARGE CELL B-CELL LYMPHOMA [DLBCL])

For categorization as MZBL of MALT-type with large cell transformation, areas of typical MZBL of MALT-type, as described above must be histologically evident. This type of primary thyroid lymphoma accounted for just under 50% of all cases in one series (36). The presence of either MZBL of MALT-type with a component of large, blastic lymphoma cells warrants a diagnosis of mixed MZBL and DLBCL. How much large cell or high-grade lymphoma has to be present to make a diagnosis? Whilst this has not been quantified widely, but general principles suggest that confluent clusters, aggregates or sheets of large cells indicate a significant component and hence designation as MZBL of MALT-type with large cell transformation. Usually an obvious cluster

Figure 8. Other cellular components of MALT-lymphoma include plasma cells, larger centroblastic cells and occasional histiocytes. These are admixed with centrocyte-like cells in MZBL of MALT-type.
Figure 9. The plasma cell component can be seen to localize around the follicle epithelium: a para-follicular location.
Figure 10. A cluster of centroblastic cells making this a mixed MZBL of MALT-type and DLBCL.
Figure 11. A reactive lymphoid follicle replete with germinal centre and mantle zone, in a MZBL of MALT-type.

or sheet or multiple areas of blast cells are encountered. In the study by Derringer and colleagues the DLBCL component accounted for at least 50% of the lymphoma (36). Thus, it would appear that the large cell component is obvious and easily discerned. The large cells may resemble centroblasts (large cells with vesicular chromatin and a small typically single nucleolus) usually, or even immunoblasts (large cells with vesicular chromatin and a prominent nucleolus) less commonly. In the series reported by Derringer et al, they even noted scattered Reed-Sternberg-like cells and cells reminiscent of the large cells seen in Burkitt's like lymphoma (36). The large cells may permeate diffusely through the thyroid with destruction of thyroid follicular epithelium or may also result in lymphoepithelial lesions (Figure 12). However, a distinct low-grade MZBL component must also be present for this lymphoma to be considered a mixed pattern.

DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) WITHOUT MZBL OF MALT-TYPE

As the name implies a histologically detectable MZBL of MALT-type as described above is not present. In a study by Skacel and colleagues, they encountered 16 cases of DLBCL without any MZBL but containing lymphoepithelial lesions composed only of large cells. These cases are more appropriately categorized as DLBCL without MZBL of MALT-type because of the absence of the latter component. Even in the absence of a low-grade component, the vast majority (85%) of DLBCL do show some of the morphological features associated with MALT-lymphoma: lymphoepithelial lesions, plasma cells, follicle colonization and monocytoid B-cells are detected although varying in number from case to case (36). In the absence ofthe MALT-lymphoma morphology, it is impossible to separate primary thyroid DLBCL from secondary involvement of the gland by a nodal primary. Careful examination of several sections may be required to find the morphological features of a MALT-lymphoma in an otherwise pervasive large cell infiltrate of the thyroid. The large cells of DLBCL are identical to the large cells described above.

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