MALIGNANT LYMPHOMA, FOLLICULAR CENTER CELL TYPE, LARGE NONCLEAVED CELL PREDOMINANT, NODULAR AND FOCALLY DIFFUSE, WITH VERY FOCAL FOLLICULAR DENDRITIC CELL PROLIFERATION AND AREAS OF SCLEROSIS, (WORKING FORMULATION: MALIGNANT LYMPHOMA, FOLLICULAR, LARGE CELL TYPE)
The histologic sections, together with the immunohistochemical stains, demonstrate a mostly nodular large noncleaved follicular center cell lymphoma that has a floral-like growth pattern within many of the nodular structures. The numerous vacuolated spaces noted in some places within the follicular structures appear to represent areas where there has been dropout of apoptotic cells, but some may also represent signet ring cells, as have been described in some follicular lymphomas. Despite attempts to label the vacuoles with kappa and lambda immunohistochemical markers, they remained predominantly negative.
The "floral" pattern of follicular center cell lymphoma (FCC) is one seen with some frequency. Although visually striking, studies have demonstrated that this variant does not differ in terms of clinical outcome from the classic type of FCC. Its importance lies in recognizing its mimicry of progressive transformation of germinal centers (a phenomenon seen in floridly reactive lymph nodes, in which small lymphocytes from the mantle zone infiltrate and distort the contours of the germinal center). It is therefore important to examine closely the morphology and distribution of the cells in the germinal centers in any case of apparent progressive transformation, so that this variant of FCC is not missed.
"Signet-ring" FCC is a well-recognized variant, in which follicular center cells contain numerous large vacuoles. Some of the vacuoles may be optically clear, while others may contain PAS-positive, "Russel-body" type inclusions. The cells containing the vacuoles in this variant are predominantly small-cleaved follicular center cells (often with the nucleus attenuated and pushed to the cellular margins by the inclusion), and are usually confined to the follicular structures. Immunohistochemical analyses have demonstrated that clear vacuoles usually contain IgG, while the PAS-positive vacuoles generally contain IgM. Usually only one type of inclusion is seen, which is consistent with the clonal nature of this follicular neoplasm. Although our case in most areas failed to stain convincingly with PAS, kappa, or lambda, the very widespread distribution of the vacuoles in the follicles of this lymphoma are most consistent with immunoglobulin production. Although this variant has not been shown to differ in prognosis with classic FCC, it is important to rule out other possibilities, most notably metastatic liposarcoma or signet ring cell carcinoma; this is accomplished through the demonstration of S100 or cytokeratin positivity on immunohistochemical staining.
The additional finding of one small area with a somewhat atypical proliferation of follicular dendritic cells is of uncertain significance in this case. Reticulum cells in lymph nodes are supportive mesenchymal cells which also have some role in the trafficking of antigens into the node and the germinal center, where they are presented to the B and T cells. There are three recognized types of reticulum cells in the lymph node; the follicular dendritic cell, the interdigitating reticulum cell, and the fibroblastic reticulum cell.
The follicular dendritic cell is a spindled cell found in the germinal center which is positive for CD21 and CD35; these cells are so closely linked physiologically and ontogenically that they are noted to proliferate in tandem with follicular center cells in follicular lymphomas. Indeed, their presence is one of the criteria for the diagnosis of a follicular center cell lymphoma over that of other types of lymphoma which do not harbor similar proliferations. Limited proliferations of follicular dendritic cells have also been noted in conjunction with the hyaline vascular variant of Castleman's disease; the inductive agent responsible for these proliferations in this setting has not been identified. True sarcoma of follicular dendritic cell origin is extremely rare, with the largest reported series consisting of 4 cases.
The interdigitating reticulum cell (IDRC)is found in the interfollicular, or T-cell areas of the lymph node, and are thought to play a role in trafficking of antigens to T cells in this area. Microscopically, the cells are often similar in appearance to the follicular dendritic cell, but may be somewhat larger, with round to spindled nuclei and more cytoplasm. Immunohistochemically, the cells are usually CD21 and 35 negative, and stain positively for S100, CD45RB, and CD68. Ultrastructurally, the cells display abundant interdigitating processes and desmosomes (hence their name), which the follicular dendritic cells lack. The IDRC also lacks Birbeck granules on ultrastructural study, distinguishing them from Langerhan's cells (which may also be numerous in nodes which receive drainage from the skin). Neoplasms of the IRDC are even less common than those of the FDC, and the distinction is made via immunohistochemical and ultrastructural study.
Lastly, the relatively newly described fibroblastic reticulum cell (FBRC) is also found in the interfollicular zones and in close association with the IDRC by desmosomal connections. Although also postulated to play a role in immune surveillance in the lymph node, the microscopic and immunohistochemical features of these cells suggest a merely structural or supportive role. The cells are invariably spindled, and stain for smooth muscle-specific actin, desmin and vimentin. They are S100, CD21 and CD35 negative. Neoplasms derived from the FBRC have been described; they tend to adopt a spindled, cartwheeling growth pattern reminiscent of metastatic malignant fibrous histiocytoma (many reported cases of MFH in the lymph node with unexplained favorable outcome may in fact have represented FBRC neoplasms). Distinction may be made by recognition of the lack of a primary extranodal site, the lack of significant "monstrocellular" atypia typical of MFH, the general lack of staining for markers of histiocytic differentiation (except occasional weak CD68 positivity) and actin/desmin positivity in the FBRC neoplasms.
Contributed by Kevin D. Horn, MD