Case 5 -
Click on each slide thumbnail image for an enlarged view
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 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
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 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
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
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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- Gupta A, Roebuck DJ, Michalski AJ. Biliary involvement in Hodgkin's disease. Pediatr Radiol 2002;32:202-204.
- Isaacson PG, Banks PM, Best PV, McLure SP, Muller-Hermelink HK, et al. Primary low-grade hepatic B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)-type. Am J Surg Pathol 1995;19:571-575.
- Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am 2000;14:579-623.
- Kyriakou D, Kouroumalis E, Konsolas J, Oekonomaki H, Tzardi M, et al. Systemic mastocytosis: A rare cause of noncirrhotic portal hypertension simulating autoimmune cholangitisóreport of four cases. Am J Gastroenterol 1998;93:106-108.
- Liangpunsakul S, Kwo P, Koukoulis GK. Hodgkin's disease presenting as cholestatic hepatitis with prominent ductal injury. Eur J Gastroenterol Hepatol 2002;14:323-327.
- Macon WR, Levy NB, Kurtin PJ, Salhany KE, Elkhalifa MY, et al. Hepatosplenic alphabeta T-cell lymphomas: A report of 14 cases and comparison with hepatosplenic gammadelta T-cell lymphomas. Am J Surg Pathol 2001;25:285-296.
- Prabhu RM, Medeiros LJ,Kumar D, Drachenberg CI, Papadimitriou JC, et al. Primary hepatic low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) associated with primary biliary cirrhosis. Mod Pathol 1998;11:404-410.
- Stancu M, Jones D, Vega F, Medeiros LJ. Peripheral T-cell lymphoma arising in the liver. Am J Clin Pathol 2002; 118:574-581.
- Wlodarska I, Martin-Garcia N, Achten R, De Wolf-Peters C, Pauwels Tulliez M, et al. Fluorescence in situ hybridization study of chromosome 7 aberrations in hepatosplenic T-cell lymphoma: Isochromosome 7q as a common abnormality accumulating in forms with features of cytologic progression. Genes chromosomes Cancer 2002;33:243-251.