Non Hodgkin lymphoma NHL

This complex group of tumors have been seen to arise from all the known lymphoid lineages (B, T, NK, mononuclear phagocytic, dendritic). The lineage of origin in a given case can usually be identified without difficulty by a modern laboratory. However such information is rarely prominent in the clinical notes, first because it is not particularly discriminatory - more than 80% of NHL in Western societies arises from the B lineage - and secondly because clinicians, encouraged by classifications such as the Working Formulation, have long correlated prognosis and management with the 'grade' of tumor (low, intermediate or high) suggested by conventional histology. However closer studies of tumor behavior, and the advent of immunotherapy, are encouraging greater interest in tumor lineage. Table 2 sets out a lineage-based subdivision of NHL, simplified from the REAL classification, which will guide our discussion here. Distinctions between the various categories depend upon histology, and upon cell

Table 2 Subdivisions of non-Hodgkin lymphoma

B Cell NHL

B Lymphoblastic B Lymphocytic Mantle-cell Follicle-center Diffuse large B cell Burkitt's

Mucosa-associated (B cell MALT lymphoma) T Cell NHL

T Lymphoblastic

Enteropathy-associated (T cell MALT lymphoma) Other peripheral T cell lymphomas markers seen either in tissue sections or dispersed cells. Some of the rarer tumors have been omitted, as have the Ig-exporting B cell lymphomas which are discussed in the next section.

B cell NHL

B lymphoblastic lymphoma is seen histologically to be composed of diffusely distributed immature cells similar to those of pre-B ALL, and the two tumors can probably be regarded as belonging to a single disease spectrum.

B lymphocytic lymphoma can similarly be regarded as a tissue equivalent of CLL, with scattered tumor masses in which infiltrates of small lymphomas efface normal lymphoid architecture. Although the leukemic component is by definition inconspicuous initially, there is a tendency to progress to a final mixed leukemia/lymphoma with widespread tumor throughout nodes, spleen and marrow. Mantle cell lymphoma is a similar tumor which usually behaves more aggressively. It is composed of small to medium lymphocytes which, like those of CLL and B lymphocytic lymphoma, display the surface molecule CD5. The cells have a mainly diffuse distribution, but sometimes congregate around normal follicular centers to form huge mantles. This striking arrangement is apparently imposed by the normal cells upon the neoplastic ones. In this tumor a characteristic translocation between chromosomes 11 and 14 is thought to activate the oncogene bcl-1.

Follicle-center lymphomas (follicular lymphomas) are the largest group of NHL occurring in Western societies. Morphologically the cells resemble a segment of that range of lymphocytes which occur normally in the germinal centers of secondary lymphoid follicles. They show a variable tendency to organize themselves into follicles. In general, among the spectrum of follicle-center lymphomas, the larger the cells and the more diffuse their organization the more aggressive the tumor. In some of the tumors there is a heavy admixture of normal T cells, whose role is obscure.

Follicle-center lymphomas are almost invariably multicentric at presentation. The clinical course varies markedly with the nature of the tumor, but most cases are fairly indolent and 5-year survivals may be expected in more than 50%. Some patients may be left untreated for a number of years, a course chosen by some physicians because, although responses to chemotherapy can be expected, extensive and prolonged remissions are unusual. Waxing and waning of the tumor masses may occur. Eventual progression of the disease is sometimes accompanied by conversion to a more malignant-looking histology, and it is likely under these circumstances that an emerging subclone has suffered additional genomic damage.

The characteristic karyotypic abnormality of follicle-center lymphomas, seen in up to 85% of cases in some series, is a reciprocal translocation between chromosomes 14 and 18. This moves the bcl-2 oncogene from its normal position on chromosome 18 into the Ig heavy-chain locus on chromosome 14. There follows an overproduction of the bcl-2 protein, which acts as a suppressor of apoptosis. The cell thereby resists the apoptotic fate of most normal follicle-center cells, a property which must contribute to growth of the tumor. Superimposed genomic damage such as mutation of the p53 suppressor gene has been associated with more aggressive behavior.

Diffuse large B cell lymphomas represent a heterogeneous group of aggressive tumors to which a variety of other names (including centroblastic and immunoblastic) have been given. The cells are larger than those of B lymphoblastic lymphoma and have a high proliferative rate. In some cases a translocation, of variable type, has been reported to activate the oncogene bcl-6. The patients often present with a single mass, and can respond well to (and even be cured by) chemotherapy.

Burkitt's lymphoma is a highly malignant extra-nodal tumor occurring mostly in children. It is composed of B lymphocytes of medium size which resemble follicle-center blasts, but are rarely seen to form follicles. The lymphoma is endemic among children in the tropical uplands of Africa and New Guinea. In these areas the tumor cells regularly contain the EBV genome. In Western societies the tumor occurs only sporadically and is associated with EBV in only a minority of cases. In both situations one sees a characteristic disturbance of the genome in which the myc oncogene (or at least its two coding exons) is translocated from chromosome 8 to one of the Ig chromosomes (14, or less commonly 2 or 22).

The high tropical incidence of the tumor probably reflects something like the following chain of events.

1. Early infection with malaria and other parasites leads to a hyperplastic lymphoid system.

2. Infection with EBV also occurs very early in life, possibly acquired via the mother's milk or saliva.

3. The virus promotes mitosis in infected B lymphocytes, but is unable by itself to promote that relentless, environmentally independent growth which constitutes neoplastic autonomy.

4. The parasite-preoccupied lymphoid system cannot generate a sufficiency of the cytotoxic T cells which normally rid the body of EBV-infected B cells.

5. The exuberant B cell mitosis greatly enhances the chance of the chromosomal translocation with myc activation which is probably the major determinant of the neoplastic transformation.

Again a superimposed mutation in the p53 suppressor gene may contribute to oncogenesis in some cases, and other genetic lesions have occasionally-been described.

Mucosa-associated B cell lymphomas (B cell MALT lymphomas) have been described in gut, salivary glands, thyroid and ocular adnexa. The histology tends to recapitulate that of the normal mucosa-associated lymphoid tissue (MALT), and the neoplastic cells tend to home to mucosal sites. Paradoxically most of these tumors arise in the stomach, which normally contains no organized lymphoid tissue. However such tissue can be acquired as a result of chronic infection with Helicobacter pylori, which has been found in association with more than 90% of the lymphomas. Low-grade tumors have been seen to regress after eradication of the bacterium. The association suggests that other causes of chronic mucosal inflammation can also predispose to MALT lymphoma.

Immunodeficiency-associated lymphomas

B cell NHL, in a variety of guises, is the most important tumor to emerge at increased incidence in states of immunodeficiency. Such states are now seen most often in association with AIDS or immunosuppression for organ grafting. The frequency with which NHL emerges appears to reflect the degree of immunosuppression, so that it is commoner following cardiac than renal grafts.

In most cases of immunodeficiency-associated lymphoma there is genomic and antigenic evidence of EBV in the tumor cells. In some cases a polyclonal lymphoproliferation is seen initially, from which a clearly monoclonal tumor may later emerge. The AIDS-associated lymphomas often exhibit also the wyc-activating translocations and histological appearances typical of Burkitt's lymphoma.

Despite the EBV association the post-transplant tumors are rarely of Burkitt type. More commonly the histology is of diffuse large B cell lymphoma, often with plasmacytoid cells present. A variety of genomic lesions have been described. Immuno-deficient states in general can also present pleomorphic lymphomas difficult to classify.

T cell NHL

T lymphoblastic lymphoma is a childhood tumor, the tissue-equivalent of T cell ALL with the cells indistinguishable. It tends to involve the thymus, to progress rapidly, and to terminate in leukemia. For reasons entirely unknown it afflicts predominantly boys.

Enteropathy-associated T cell lymphomas are generally seen as jejunal tumors associated with celiac disease. The latter is a malabsorptive state of puzzling pathogenesis, with features of both hypersensitivity (resolution upon elimination of gluten proteins from the diet) and autoimmunity (a strong association with certain major histocompatibility complex (MHC) class II alleles, the presence of reticulin specific antibodies, and heavy lymphocytic infiltration of the jejunal epithelium). It seems likely that the tumor is preceded by the celiac disease and arises from the infiltrating lymphocytes. The tumor cells are of various sizes, sometimes pleomorphic. Jejunal ulceration and perforation often supervene.

Other T cell lymphomas are often lumped together as peripheral T cell lymphomas. They are a heterogeneous and confusing group, from which a few striking tumors stand out. Angioimmunoblastic lymphoma displays amid the neoplastic cells an expansion of high endothelial venules, the specialized vessels of T cell areas in lymphoid tissue through which lymphocytic migration from the blood occurs. In angiocentric lymphoma the neoplastic cells invade and occlude blood vessels, leading to ischemic necrosis. Anaplastic large-cell lymphoma is marked by a consistent and striking display of CD30, an activation antigen first observed in Hodgkin's disease. The cells are unusually large, have a variable display of T cell antigens, and often involve nodal sinuses and extranodal sites.

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