—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 5 - Hematolymphoid Neoplasms

Larry Burgart
Mayo Clinic
Rochester, MN


Click on each slide thumbnail image for an enlarged view
Clinical History
A 39 year old man presented with fatigue, pruritis and weight loss. Physical exam revealed low grade ascites, mildly enlarged liver and splenomegaly. Alkaline phosphatase was 2.5x normal and transaminases were barely out of the normal range.


Case 5 - Figure 1 - Edematous portal tract with moderate inflammatory infiltrate
Case 5 - Figure 2 - Minimal lobular hepatitis
Case 5 - Figure 3 - Mononuclear inflammatory infiltrate with bile duct injury


Case 5 - Figure 4 - Periportal expansion with relatively modest inflammatory infiltrate
Case 5 - Figure 5 - Periportal expansion with relatively modest inflammatory infiltrate
Case 5 - Figure 6 - Periportal expansion with relatively modest inflammatory infiltrate

Discussion
Hematolymphoid neoplasms involving the liver can manifest several different patterns which should alert the pathologist to the possibility of lymphoma or leukemia despite significant morphologic overlap with nonneoplastic (so-called medical) inflammatory liver diseases. The most straightforward situation is diffuse large B-cell lymphoma producing a solitary tumor mass. This is an uncommon presentation but biopsy is clearly indicative of large cell neoplasm which requires only immunophenotypic confirmation for a final diagnosis. The two patterns which will be discussed further in this talk are portal-based infiltrates.

Portal-based hematolymphoid neoplasms are typically of lymphoid histogenesis. A significant subset of these cases can be quite subtle, mimicking quiescent hepatitis or chronic biliary disease. The most subtle among these, and fortunately relatively uncommon, is mast cell disease involving the liver. Mast cell disease is an excellent mimic of primary sclerosing cholangitis or, less commonly, primary biliary cirrhosis. The typical neoplastic mast cell is a medium-sized ovoid cell with moderate nuclear to cytoplasmic ratio. The neoplastic mast cells are typically admixed with edema, eosinophils and scattered lymphocytes. Ductopenia is uncommon although lymphocytic cholangitis may be focally present. Overt granulomatous cholangitis (florid duct lesions) is not identified. However, the lack of prominent hypercellularity, the admixture of inflammatory cells (including apparent histiocytes) and the portal/periportal expansion without accompanying hepatitis are all suggestive of chronic biliary disease. Making the appropriate diagnosis requires some level of consideration of mast cell disease in cases of early stage chronic biliary disease. The neoplastic mast cells are not granular and do not stain reliably with Giemsa. Tryptase or c-kit (CD117) immunohistochemical stains are most reliable in confirming the diagnosis. Mast cells are very few in number in inflammatory liver diseases.

Classical Hodgkin lymphoma is another mimic of chronic biliary disease. Hodgkin lymphoma is typically confined to the biliary tree although some of the expanded portal tracts can become tumefactive which may simplify the diagnosis. When the neoplasm is more broadly distributed among interlobular and septal portal tracts, the lymphohistiocytic background can be an excellent mimic of primary biliary cirrhosis, including damage to the bile duct epithelium. In extranodal sites, the neoplastic Hodgkin cells, including Reed-Sternberg cells and variants, are often few in number. Therefore, neoplastic cytology is typically not an initial clue to the correct diagnosis. Hodgkin lymphoma infiltrates have a more prominent and uniform histiocyte content than primary biliary cirrhosis. Recognition of this subtle difference in inflammatory cell content and a low threshold for suspicion should elicit an immunophenotypic workup to identify diagnostic Reed-Sternberg cells which are characteristically CD30-positive, CD15-positive and uniformly CD45-negative.

A significant minority of chronic lymphocytic leukemia (CLL) patients have an elevated alkaline phosphatase. This usually correlates with neoplastic small lymphocytes infiltrating the portal tracts. While this may cause an expansile infiltrate, it most typically manifests as nonspecific monomorphic portal infiltrates without lymphocytic cholangitis or portal expansion. Liver involvement by CLL is best documented by demonstrating co-expression of CD20 and CD5 by the monomorphic small lymphocytes. Although this causes alkaline phosphatase elevation and may cause pruritus, minor hepatic involvement by CLL does not appear to be an adverse prognostic indicator.

Extranodal marginal zone lymphoma of MALT-type (MALToma) has rarely been reported in the liver. It has been described, and occasionally noted in association with primary biliary cirrhosis. Suspicion should be raised if there is a prominent expansion of marginal zone around portal-based lymphoid follicle or an exceptionally large lymphoid aggregate with monocytoid cytology. Confirmation of diagnosis will require demonstration of a B-cell phenotype and clonal immunoglobulin light chain expression.

A very interesting but much different pattern of lymphomatous involvement of the liver is sinusoidal lymphocytosis. In general, this pattern is characterized by increased mononuclear cells throughout the sinusoids, with no zonal predilection. This infiltrate gives the appearance of a string of pearls, although less commonly there can be aggregation of the neoplastic cells within the sinusoids as well. Sinusoidal lymphocytosis can be seen in systemic infectious processes such as Epstein-Barr virus (infectious mononucleosis) or mild infiltrates can occur with "hepatic involvement by systemic inflammatory conditions" such as collagen vascular diseases. Almost any hematolymphoid neoplasm can present with this pattern although the most characteristic diagnoses are hepatosplenic T-cell lymphoma, peripheral T-cell lymphoma unspecified and leukemias, either acute or chronic. Anaplastic (CD30-positive) large cell lymphoma and various mature B-cell lymphomas including large cell lymphoma and follicular lymphoma have also rarely presented with sinusoidal lymphocytosis.

The overt leukemic processes (including acute myelogenous leukemia, chronic myelogenous and myelomonocytic leukemias and acute lymphocytic leukemias) are usually easily identified based on marked hypercellularity and cytologic atypia.

The most problematic differential diagnosis is T-cell lymphoma versus infectious or reactive infiltrates. The cellularity of hepatosplenic T-cell lymphoma or other peripheral T-cell lymphomas tend to be at most moderate with significant overlap of what can be seen in reactive processes. The cytology in these neoplasms is medium cell size usually with mild to moderate atypia. Because of this overlap, demonstration of clonality or cytogenetic abnormalities are often needed to confirm the diagnosis. Immunophenotypic demonstration of cytotoxic phenotype in hepatosplenic T-cell lymphoma may be helpful but it should be borne in mind that the reactive processes mentioned also consist predominately of cytotoxic T-cells, which will express cytotoxic granule markers including Tia-1 and granzyme B. Therefore, the diagnosis will rest on molecular genetic demonstration of T-cell receptor gene clonality or characteristic cytogenetic abnormality such as isochrome 7 in hepatosplenic T-cell lymphoma.

In summary, portal- and sinusoidal-based hematolymphoid neoplasms can have significant overlap with reactive processes. With portal-based lymphoid neoplasms, a low threshold for suspicion is helpful in inducing appropriate immunophenotypic workup. Awareness of sinusoidal lymphocytosis as a common pattern for lymphoma and leukemia will also allow for appropriate workup but one must be careful not to overdiagnose reactive process as lymphoma.

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