Histological findings, general approach
Lymphomas of the liver are divided into Hodgkin and non-Hodgkin types, and the non-Hodgkin category is further subclassified into B- and T-cell types. The diagnosis can usually be established based on morphology and routine immunohistochemistry, although sometimes molecular genetics and/or interphase FISH studies must be employed. Pan-B-cell markers include CD19, CD20, CD22, CD79a, and PAX-5, and pan-T-cell markers include CD2, CD3, CD5, and CD7. Of these, starting with CD20 and CD3 is a common and practical approach. Useful plasma cell markers include MUM1 and CD138, although hepatocytes and bile ducts will also be positive for CD138, and B-cells and T-cells may be positive for MUM1. Light chain restriction of B-cells and/or plasma cells can be evaluated using immunostains for kappa and lambda immunoglobulin light chains. Histiocyte markers include CD68 and CD163, among others. If classical Hodgkin lymphoma is in the differential diagnosis, helpful immunostains include CD3, CD20, CD15, CD30, CD45, and PAX-5.
Lymphomas differ in their general patterns of liver involvement.1
Although there are exceptions, these general patterns provide a useful starting point when evaluating a case (Table 30.4
Differential, general considerations
The histological differential typically depends on the degree of tumor differentiation and on the presence or absence of a mass lesion, but overall falls into four different categories.
Table 30.4 Patterns of growth in the liver
Portal tract predominant
Mass lesion predominant
Peripheral T-cell lymphoma, NOS
Diffuse large B-cell lymphoma
Hepatosplenic T-cell lymphoma
Marginal zone lymphoma
Hairy cell leukemia
Anaplastic large cell lymphoma
Mantle cell lymphoma
B lymphoblastic leukemia/lymphoma
T-Cell/histiocyte-rich large B-cell lymphoma
1. Well differentiated mass lesion: When there is a mass lesion composed of well differentiated cells, the differential tends to be that of malignant lymphoma, inflammatory pseudotumor, Castleman disease, or benign reactive lymphoid hyperplasia.
2. Poorly differentiated mass lesion: In contrast, when there is a mass lesion composed of poorly differentiated, cytologically atypical cells, the differential is primarily that of malignant lymphoma versus carcinoma, follicular dendritic cell sarcoma or other sarcomas, or melanoma, a differential that can usually be resolved by immunohistochemistry and/or molecular studies.
3. Sinusoidal pattern: When there is no mass lesion, the differential depends on the location of the infiltrates. With predominantly sinusoidal disease, the differential is that of hepatitis versus lymphoma/leukemia.
4. Portal-based pattern: With no mass lesion and predominantly portal-based disease, the differential includes chronic hepatitis with prominent lymphoid aggregates/follicles, B-cell lymphomas, and classical Hodgkin lymphoma.
These four general scenarios are discussed next. In the first setting, a mass-forming lesion can have a differential of a reactive condition, such as inflammatory pseudotumor, Castleman disease, or reactive lymphoid hyperplasia, versus malignant lymphoma.
Most inflammatory pseudotumors can be separated from lymphomas by their mixed inflammatory infiltrates, which are composed primarily of T lymphocytes with scattered B-cell aggregates, and prominent admixed plasma cells. These inflammatory changes are seen against a backdrop of spindled myofibroblasts and variably dense collagenous deposits. Many inflammatory pseudotumors have inflammation and sclerosis of central veins, though these areas may not be sampled in biopsy material. Classical Hodgkin lymphoma and B-cell lymphomas such as T-cell/histiocyte-rich large B-cell lymphoma should be carefully ruled out by histologic review and immunohistochemistry if necessary, although these disorders typically present as portal-based disease rather than a mass lesion. The differential diagnosis also includes Castleman disease (see discussion above).
In the second setting, the hematoxylin and eosin (H&E) findings are clearly malignant and the differential is typically large cell lymphoma (usually diffuse large B-cell lymphoma) versus sarcoma, a poorly differentiated carcinoma, or melanoma. Immunohistochemistry will lead to the correct diagnosis in most cases. Burkitt lymphoma can also present as a mass lesion, although other large cell lymphomas, such as anaplastic large cell lymphoma, are rare in the liver. Of note, one immunostain pitfall is that a subset of diffuse large B-cell lymphomas can be p63-positive. Also, B-cell lymphomas that have been previously treated with rituximab may recur as CD20-negative B-cell lymphomas. As another diagnostic pitfall, lymphocyte-rich hepatocellular carcinomas have dense sinusoidal infiltrates of lymphocytes that can be mistaken for lymphoma. However, the lymphocytes are primarily cytologically bland T-cells with scattered small aggregates of B-cells and occasional lymphoid follicles. The hepatocytes will show architectural and cytological atypia.
In the third setting, with a sinusoidal pattern of disease, important clues to possible malignancy include lymphocytes that have either too much cytoplasm or show significant nuclear atypia. Another finding that suggests malignancy is unusually dense sinusoidal cellularity with relatively little hepatocyte injury. Atypical patterns of lobular necrosis can also be an important observation, as necrosis in the setting of marked hepatitis tends to begin in zone 3. Zone 1 predominant necrosis or nonzonal necrosis (outside the setting of panacinar necrosis) are unusual for the hepatotropic viruses (A, B, C, E), autoimmune hepatitis, or drug induced hepatitis and such cases benefit from workup to exclude lymphoma. Infarct-like coagulative necrosis in the setting of marked inflammation also can be seen with lymphomas.
In the fourth setting, liver specimens show no mass lesions, but on histological examination there are lymphoid infiltrates predominantly in the portal tracts. The differential is primarily chronic hepatitis (e.g., viral, autoimmune, etc.) versus a B-cell lymphoma, such as a small B-cell lymphoma or T-cell/histiocyte-rich large B-cell lymphoma, versus classical Hodgkin lymphoma. Because many primary B-cell lymphomas arise in the setting of chronic viral hepatitis, positive viral serology does not rule out lymphoma. The lymphoid aggregates in chronic viral hepatitis tend to be scattered and small and involve medium-sized and larger sized portal tracts. For this reason, diffuse portal tract involvement, or unusually large aggregates, can be important clues to a diagnosis of lymphoma. Cytological monotony or cytological atypia can also suggest a diagnosis of lymphoma. Challenging cases often show borderline findings on H&E, with only mild atypia. Most borderline cases are classified as benign on further work up, but a subset are lymphoma and borderline cases benefit from further evaluation.
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