Early lesions characteristically show retention of the architecture of involved tissues. Where lymph nodes are involved, the sinuses remain patent, and there is no extension beyond the capsule into adjacent tissues (Fig. 9.1). Reactive or hyperplastic germinal centers may be present. In plasma cell hyperplasia there are sheets of plasma cells but no architectural effacement (Fig. 9.2). Early lesions should be poly- or oligoclonal, and there should be no structural alterations in oncogenes or tumor suppressor genes. The adenotonsillar region is an important localization site for early lesions (Fig. 9.3), which tend to involve younger patients relatively soon after transplantation [9]. Patients with localized adenotonsillar PTLDs are more often females, and the outcome is generally favorable. PTLDs that resemble infectious mononucleosis are characterized by paracortical expansion (see Fig. 9.2) and a mixed population of lymphoid cells and plasma cells as well as immunoblasts, which may be numerous.

Polymorphic PTLDs (PL) include a broad spectrum of lymphoid proliferations with variable histologic appearance (Figs. 9.4, 9.5, 9.6, 9.7, 9.8, and 9.9). PL is frequently extranodal, including involvement of the gastrointestinal tract and the transplanted organ. The proliferations tend to occur relatively early after transplantation, overlapping with the early lesions. They may resolve with conservative therapy, but behavior is difficult to predict and dissemination may occur, including involvement of the central nervous system.

PL causes effacement of architecture by a proliferation that includes small lymphocytes, plasma cells, histiocytes, and variable numbers of transformed lymphoid cells and immunoblasts. There may be varying degrees of cytologic atypia, including the presence of Hodgkin and Reed Sternberg-like cells (Fig. 9.10). Areas of necrosis are frequently present. In addition to expression of EBV EBER, the large cells are often positive for EBV latent membrane protein (LMP1).

Despite the polymorphous appearance, PL is predominantly monoclonal in terms of immunoglobulin gene rearrangements and light-chain expression (Fig. 9.11) as well as EBV clonality, but lacks structural abnormalities in oncogenes or tumor suppressor genes. Mutations in the BCL6 gene are sometimes found, although they lack BCL6 rearrangement [10, 11].

Monomorphic PTLDs (ML) usually develop in older patients after a longer interval following transplantation. The lymphomas may be of B- or T-cell origin, and the T-cell types are described below. ML resembles aggressive forms of lymphoma encountered in the general, nontransplant population, particularly diffuse large B-cell lymphoma (DLBCL), and is classified according to the WHO [1]. It may present in lymph nodes and bone marrow as well as extranodal sites and may be disseminated involving the bone marrow. Different clones may be found at different sites of disease in the same patient with multifocal involvement. ML tends to have an aggressive course requiring systemic chemotherapy. It is composed of sheets of large malignant cells that may be centroblastic or immunoblastic in appearance (Figs. 9.12, 9.13, and 9.14). In addition to monoclonal immunoglobulin gene rearrangements, it often contains structural abnormalities in oncogenes or tumor suppressor genes, including MYC, TP53, and RAS.

Plasmablastic PTLDs are an unusual form of monomorphic B-cell PTLDs. Most cases have been reported in male patients, and most are associated with EBV [12]. They are composed of sheets of blastic cells with prominent nucleoli and plasmacytoid cytoplasm (Fig. 9.15). They may express CD138 and be negative for CD20, and they are usually positive for EBV (Fig. 9.16). MYC/IGH rearrangements are seen in about one third of cases. Long-term remissions have been achieved, usually in combination with chemotherapy and reduced immunosuppression. Non–EBV-positive cases and those with cytogenetic abnormalities may have a worse prognosis.