Hematopathology and the Liver
Michael S. Torbenson
Ellen D. McPhail
30.1 OVERVIEW
The liver can be involved by reactive lymphoid hyperplasia and by various hematological malignancies. The appropriate diagnosis can be very challenging and often requires careful correlation with clinical, imaging, and laboratory findings. Leukemia represents secondary involvement of the liver, while lymphomas can be either primary or secondary to the liver. Most primary lymphomas of the liver are non-Hodgkin lymphoma, and about two-thirds are first diagnosed at liver biopsy.1 The most common primary B-cell lymphoma of the liver is diffuse large B-cell lymphoma (approximately 75% of cases), followed by marginal zone lymphoma (approximately 20%).2, 3, 4, 5 About 5% of primary hepatic lymphomas are Burkitt lymphoma,2,4 with the remaining entities all contributing 1% or less.
30.2 REACTIVE HEMATOLOGICAL DISORDERS
Hematological disorders of many different types are associated with vascular flow changes to the liver, even if the disease itself does not directly involve the liver. The frequency and types of changes are variable, depending on the hematological disease, but include portal venopathy, nodular regenerative hyperplasia, and veno-occlusive disease. Each of these entities is considered in more detail in their respective chapters. Amyloid deposition is another important process that can result from hematological disorders.
Reactive conditions
The most common reactive hematopoietic conditions found in liver biopsies are extramedullary hematopoiesis, Kupffer cell hyperplasia, and the hemophagocytic syndrome. Extramedullary hematopoiesis can include myeloid precursors, red blood cell precursors, and/or megakaryocytes (Fig. 30.1). Extramedullary hematopoiesis is not a disease entity per se, but instead is a secondary manifestation of both benign and malignant conditions. In infants and children, extramedullary hematopoiesis is commonly found in a variety of liver diseases, but in particular cholestatic diseases. Even in adults, cholestatic liver disease can occasionally be accompanied by mild extramedullary hematopoiesis. Extramedullary hematopoiesis can also be found in
diseases with impaired red blood cell synthesis, including the chronic hemolytic anemias and hemoglobinopathies. Finally, extramedullary hematopoiesis can result from malignant conditions involving the bone marrow, such as chronic myeloproliferative neoplasms or myelophthisic processes such as lymphomas or carcinomas.
diseases with impaired red blood cell synthesis, including the chronic hemolytic anemias and hemoglobinopathies. Finally, extramedullary hematopoiesis can result from malignant conditions involving the bone marrow, such as chronic myeloproliferative neoplasms or myelophthisic processes such as lymphomas or carcinomas.
 Figure 30.1 Extramedullary hematopoiesis. Red blood cell precursors are seen in the sinusoids. |
Kupffer cell hyperplasia
Generalized Kupffer cell hyperplasia is a common secondary event in cholestatic conditions and with marked hepatitis. Kupffer cell hyperplasia outside of these settings is most commonly seen with acute viral hepatitis, such as cytomegalovirus (CMV) or Epstein-Barr virus (EBV), and can be accompanied by hemophagocytosis. When hemophagocytosis is prominent, a diagnosis of hemophagocytic syndrome should be considered. In one study, 1.6% of sequential nontumor liver biopsies showed Kupffer cell hyperplasia with hemophagocytosis.6 The hemophagocytic syndrome results from uncontrolled macrophage activation and is seen as either as a primary (familial) disease or as a secondary disease.
Secondary hemophagocytic syndrome
The secondary hemophagocytic syndrome can be seen with many different underlying disease conditions (Table 30.1), but most can be categorized as infections, malignancies, autoimmune conditions, or drug effects. The histological findings will vary, depending on the underlying disease conditions, but all share the findings of Kupffer cell hyperplasia and hemophagocytosis (Fig. 30.2). The hemophagocytosis should be convincing because Kupffer cell hyperplasia without hemophagocytosis is also common in many different inflammatory and cholestatic diseases of the liver.
The list of infections associated with the secondary hemophagocytic syndrome is very long and seems to grow ever longer, including both infections passed from human to human as well as many zoonotic infections.7 Overall, EBV and CMV are the most common triggers in nonimmunosuppressed patients. In immunosuppressed patients, a
much wider range of infectious associations are found. In fact, the frequency of secondary hemophagocytic syndrome on liver biopsy is particularly high with HIV infection, up to 8%.6 In most HIV cases, an infectious trigger is eventually identified and can be viral or bacterial.
much wider range of infectious associations are found. In fact, the frequency of secondary hemophagocytic syndrome on liver biopsy is particularly high with HIV infection, up to 8%.6 In most HIV cases, an infectious trigger is eventually identified and can be viral or bacterial.
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 Figure 30.2 Kupffer cell hyperplasia with hemophagocytosis. The Kupffer cells are very prominent and some have phagocytized red blood cells. |
Overall, about one-third of individuals with secondary Kupffer cell hyperplasia and hemophagocytosis on liver biopsy will have additional findings that fulfill the criteria for the complete hemophagocytic syndrome (Table 30.2).6 Nonetheless, cases that don’t fulfill the full criteria typically have some of the findings seen in Table 30.2 and overall there appears to be a continuum, with the full hemophagocytic syndrome at the severe end. Secondary hemophagocytic syndromes are generally managed through treatment of the underlying disease process.
Familial hemophagocytic lymphohistiocytosis
Familial hemophagocytic lymphohistiocytosis typically affects children less than 2 years of age. Familial hemophagocytic lymphohistiocytosis is rapidly fatal if untreated by immunosuppression and bone marrow transplant. Familial hemophagocytic lymphohistiocytosis can result from mutations in a number of different genes that impair the function of T-cells and NK-cells, including PRF1 (encode perforin), UNC13D, STXBP2, and STX11. Overall, genetic mutations are found in about 65% of cases, with the remaining presumably having mutations in unknown genes. The diagnosis is made either by identifying mutations or by clinical criteria employed in clinical trials (Table 30.2). Because not all affected individuals will meet these criteria, in particular at first presentation, a modified set of criteria has been suggested for routine clinical care (Table 30.3).
Table 30.2 Criteria for Hemophagocytic Lymphohistiocytosis. Five of Eight Are Needed for a Diagnosis | ||||||||||||||||||||||||||||||
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Familial hemophagocytic lymphohistiocytosis is typically associated with hepatomegaly and liver dysfunction that ranges from mild to severe. Histologically, there can be several different patterns of injury, but common to all of these patterns are the core findings of hemophagocytosis, bile duct lymphocytosis and injury, and significant endothelialitis.8 In addition to phagocytosis of red blood cells, phagocytosis of leukocytes can be observed.
Some cases show a chronic hepatitis pattern, with portal tract infiltrates that in most cases are moderate to marked.8,9 The inflammation is predominantly lymphocytic with varying numbers of histiocytes. Plasma cells, eosinophils, and neutrophils are rare. Almost all cases show bile duct lymphocytosis and injury. In addition, endothelialitis is present in almost all cases and can involve the central veins or the portal veins. In some cases, the phlebitis can be marked, with necrosis of the vein and surrounding parenchyma. The lobules can show mild zone 1 macrovesicular steatosis. The sinusoidal lymphohistiocytic infiltrates can be striking, resembling a leukemic infiltrate, or
can be more subtle and patchy. Hemophagocytosis is universally present.
can be more subtle and patchy. Hemophagocytosis is universally present.
Table 30.3 Modified criteria for hemophagocytic lymphohistiocytosis | ||||||||||||||||||||||||||||||||||||
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A second major pattern, found in about 25% of cases, is that of giant cell hepatitis, which histologically can be essentially identical to idiopathic neonatal giant cell hepatitis. Both show similar lobular cholestatic changes and giant cell transformation of hepatocytes. However, idiopathic neonatal giant cell hepatitis typically lacks the endothelialitis and hemophagocytosis seen in familial hemophagocytic lymphohistiocytosis. Also, the lymphohistiocytic infiltrates are denser in most cases of familial hemophagocytic lymphohistiocytosis than they are in idiopathic neonatal giant cell hepatitis. Nonetheless, some cases have sufficient overlap that correlation with the clinical and laboratory findings are needed to clarify the diagnosis.
 Figure 30.3 Crystal storing histiocytosis. The Kupffer cells have dense, eosinophilic inclusions. |
In a third pattern, the histiocytic component is sufficiently prominent to suggest a storage disease.8 The histiocytic cells in the sinusoids have abundant cytoplasm that takes on an eosinophilic color, making them hard to distinguish from hepatocytes. Also, the histiocytic inflammation can fill the terminal hepatic venules in a subset of cases, suggesting a veno-occlusive injury.
Crystal storing histiocytosis
Crystal storing histiocytosis is a rare condition where the Kupffer cells of the liver are enlarged and distended with pink, chunky material (Fig. 30.3). On high-power examination, striations can be found in many cases (Fig. 30.4). One study found that crystals also involved
the hepatocytes.10 The material in most cases represents kappa immunoglobulin light chain, but rarely other material has been reported, including clofazimine crystals, cysteine, and silica.11 In most cases, there is a history of multiple myeloma, lymphoplasmacytic lymphoma, or monoclonal gammopathy of undetermined significance.11 The deposits in crystal storing histiocytosis are commonly not limited to the liver, and involve multiple organs. Overall, the bone marrow, liver, lymph nodes, spleen, and kidney are the most commonly affected sites.11
the hepatocytes.10 The material in most cases represents kappa immunoglobulin light chain, but rarely other material has been reported, including clofazimine crystals, cysteine, and silica.11 In most cases, there is a history of multiple myeloma, lymphoplasmacytic lymphoma, or monoclonal gammopathy of undetermined significance.11 The deposits in crystal storing histiocytosis are commonly not limited to the liver, and involve multiple organs. Overall, the bone marrow, liver, lymph nodes, spleen, and kidney are the most commonly affected sites.11
 Figure 30.4 Crystal storing histiocytosis. Striations can be seen in some cases under high magnification. |
Rosai-Dorfman disease
Rosai-Dorfman disease is also known as sinus histiocytosis with massive lymphadenopathy and is a histiocytic disorder of unknown etiology. Overall, the disease appears to be more common in children than adults. Most individuals are immunocompetent and the male to female is about equal. The clinical findings at presentation are variable, but can include fever, weight loss, lymphadenopathy, and elevated liver enzymes.12 Coexisting lymphomas in other organ systems have also been reported.13,14 The disease only rarely involves the liver, and when it does, it is typically part of systemic disease. Other organs commonly involved by Rosai-Dorfman disease include the lymph nodes, skin, and upper respiratory tract. The disease course is quite variable: there can be spontaneous resolution, but rare cases can lead to death.
On liver biopsy, Rosai-Dorfman disease not only typically involves primarily the portal tracts (Fig. 30.5) but also has patchy infiltrates in the lobules. Rarely, a mass lesion in the liver is found.15 The infiltrates can resemble ordinary hepatitis, with admixed lymphocytes, plasma cells, and eosinophils that largely obscure the histiocytic infiltrates. In other cases, the histiocytes are more evident and can even be granulomatous.15 The histiocytes may have mild nuclear irregularities. Their cytoplasm is typically moderate to abundant and a clear or a pale, eosinophilic color. Emperipolesis is common. Bile duct damage is often found and can be striking. In many cases, the portal veins can be atrophic or absent in the affected portal tracts. The abnormal histiocytes stain strongly with S-100 (Fig. 30.6) and CD68 but are negative for CD1a.
 Figure 30.5 Rosai-Dorfman disease. The portal tracts show a dense infiltrate of macrophages, lymphocytes, and plasma cells. |
 Figure 30.6 Rosai-Dorfman disease, S100. The histiocytes are strongly S100-positive. |
Castleman disease (angiofollicular hyperplasia)
Definition
Castleman disease is a benign disease characterized by follicular hyperplasia and regressively transformed germinal centers.
Clinical findings
Castleman disease can involve the liver parenchyma or the hilar lymph nodes.16 Imaging studies often suggest hepatocellular carcinoma.17, 18, 19 Clinically, Castleman disease is commonly divided into localized versus multicentric disease. In some classification systems, Castleman disease is further divided into those cases that are human herpesvirus 8 (HHV8) positive or negative. Unicentric Castleman disease commonly presents in younger adults as a localized mass, typically involving the mediastinum, but without systemic symptoms. Most of these cases are classified histologically as the hyaline vascular type.
Multicentric disease has a more aggressive clinical course and is treated with systemic therapies. Most of
these cases are classified histologically as plasma cell Castleman disease. Multicentric disease is often associated with systemic signs and symptoms, including generalized lymphadenopathy, fevers, night sweats, weight loss, and fatigue. Affected individuals often have anemia and hypergammaglobulinemia. Some individuals with the plasma cell variant of Castleman disease will have the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin lesions) syndrome. HHV8 infections are more common in the plasma cell variant, often in the setting of HIV infection, solid organ transplantation, or other immunosuppressed conditions.
these cases are classified histologically as plasma cell Castleman disease. Multicentric disease is often associated with systemic signs and symptoms, including generalized lymphadenopathy, fevers, night sweats, weight loss, and fatigue. Affected individuals often have anemia and hypergammaglobulinemia. Some individuals with the plasma cell variant of Castleman disease will have the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin lesions) syndrome. HHV8 infections are more common in the plasma cell variant, often in the setting of HIV infection, solid organ transplantation, or other immunosuppressed conditions.
Gross findings
Not all lesions are grossly visible. When they are, the lesions are often subcapsular, soft, and tan-yellow. Most are less than 2 cm in size.
Microscopic findings
The core histological pattern is that of florid lymphoid hyperplasia, including follicles with regressively transformed germinal centers and increased vascularity in the interfollicular spaces. Four histological types have been recognized: hyaline vascular type, plasma cell type, mixed type, and plasmablastic type.
The hyaline vascular type is the most common, tends to be localized, has few symptoms, and has a good prognosis. Histologically, hyaline vascular Castleman disease tends to involve the portal tracts, showing lymphoid hyperplasia with regressively transformed germinal centers. The regressively transformed germinal centers are depleted of lymphocytes and composed mostly of follicular dendritic cells, giving the center a hyalinized appearance. These regressed germinal centers are often surrounded by an expanded mantle zone with concentric rings of lymphocytes, a finding that has been described as an “onion skin” appearance. Finding multiple regressively transformed germinal centers within a single mantle zone is essentially pathognomonic for Castleman disease. The interfollicular areas are hypervascular. Sometimes the blood vessels from the hypervascular interfollicular region penetrate the regressively transformed germinal centers at right angles, leading to a “lollipop” appearance.
Plasma cell Castleman disease is more likely to cause symptoms and to be multicentric, thus is more commonly encountered in liver specimens. Plasma cell Castleman disease also shows follicular lymphoid hyperplasia but has significantly fewer regressively transformed germinal centers than the hyaline vascular type. In addition, the interfollicular space and subcapsular sinuses may have sheets of plasma cells.
The mixed subtype shows areas of both hyaline vascular and plasma cell types. HHV8-positive multicentric Castleman disease, a rare disease with an aggressive clinical course, contains plasma cells with a plasmablastic appearance.
Other findings
Castleman disease, in particular with multicentric disease and the plasma cell subtype, can be associated with other patterns of liver injury, even if the liver is not directly involved by the Castleman disease. These changes fall largely into the category of vascular abnormalities, including Budd-Chiari syndrome,20 nonspecific sinusoidal dilatation,21,22 peliosis hepatis,23, 24, 25 and nodular regenerative hyperplasia.24 Hepatic amyloid deposition, usually AA type, has also been well described.26, 27, 28 Regression of the AA amyloid deposits has been observed following successful treatment of the Castleman disease.29
Differential diagnosis
The florid lymphoid hyperplasia seen in Castleman disease can mimic both reactive lymphoid hyperplasia as well as B-cell lymphomas, including follicular lymphoma and mantle cell lymphoma. Identifying the regressed germinal centers, including multiple regressively transformed germinal centers within a single mantle zone, and vascular hyperplasia in the interfollicular spaces will separate Castleman disease from reactive lymphoid hyperplasia. In addition, sheets of plasma cells in the subcapsular sinuses are characteristic of the plasma cell type of Castleman disease. Finally, HHV8 positivity in the setting of HIV infection favors Castleman disease. The typical histology of Castleman disease can differentiate it from B-cell lymphomas, but immunohistochemistry can be very helpful in difficult cases.
Reactive lymphoid hyperplasia
Definition
A small, benign, well-circumscribed nodule of reactive lymphoid follicles.
Clinical findings
Reactive lymphoid hyperplasia is also called pseudolymphoma and nodular lymphoid lesion of the liver. The term pseudolymphoma is perhaps best avoided,
as the term can be confusing to clinical colleagues. The lesion is very rare, with about 50 cases reported in the literature.
as the term can be confusing to clinical colleagues. The lesion is very rare, with about 50 cases reported in the literature.
Reactive lymphoid hyperplasia is commonly misdiagnosed as hepatocellular carcinoma, cholangiocarcinoma, or metastatic disease on imaging studies. The mean age at presentation is approximately 55 years, range 15 to 85 years, and there is an 8 to 1 female predominance.32 Reactive lymphoid hyperplasia also occurs in other organs, such as the lung, skin, and gastrointestinal tract. However, in most reported cases, reactive lymphoid hyperplasia of the liver is restricted to the liver and there is no multiorgan disease. The etiology of reactive lymphoid hyperplasia is unclear, but at least in part appears to result from a localized immunological response to various infection antigens, neoplastic antigens, or autoimmune antigens. Reactive lymphoid hyperplasia is seen most commonly in either the setting of malignancies in other organ systems (most commonly the stomach or kidney) or in a variety of autoimmune conditions, some that are systemic, such as common variable immunodeficiency (CVID), and others that are hepatic, such as primary biliary cirrhosis.
Gross findings
The lesion(s) can be single (80%) or multifocal (20%). When multifocal, cases to date have had either two or three lesions. The lesions are well circumscribed, yellow, and soft to firm. Many have a subcapsular location and almost all reported lesions are 2 cm or less in size. The largest case reported to date measured 5.5 cm.33
Histology findings
Histologically, reactive lymphoid hyperplasia is composed of a well circumscribed cluster of reactive lymphoid follicles. The follicles have polarized germinal centers that contain a mixture of centroblasts and centrocytes with admixed tingible-body macrophages. The germinal centers are surrounded by reactive mantles and the follicles lack the back-to-back arrangement seen in follicular lymphoma. They are nonclonal by immunohistochemical or polymerase chain reaction (PCR) studies.
Rare cases can have prominent histiocytic infiltration within the lesion or have focal areas of granulomatous inflammation.34 In some cases, there can be microcalcifications.33 Reactive bile ductules are common at the interface with the background liver and rare cases can have psuedocapsules of compressed fibrotic tissue.33 Although lesions are generally well circumscribed, the portal tracts adjacent to the lesions can show increased chronic inflammation. The background liver is either normal or shows changes of underlying disease, such as chronic viral hepatitis or primary biliary cirrhosis. When there is underlying liver disease, the changes in the background liver are typical for that disease, with no unusual features.
Differential
The differential includes Castleman disease, but reactive lymphoid hyperplasia lacks the regressed germinal centers and the interfollicular vascular hyperplasia. One reported case of reactive lymphoid hyperplasia had interfollicular plasma cells,35 but most cases lack the sheets of plasma cells in the interfollicular spaces and subcapsular sinuses that are typical of the plasma cell variant of Castleman disease. Lymphoma can be excluded by immunostains and molecular testing, with the differential primarily that of follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.
30.3 MALIGNANT LYMPHOMA: GENERAL CLINICAL AND PATHOLOGIC FINDINGS
Definition
Lymphomas and leukemias are neoplastic proliferations arising from cell types within the hematopoietic system.
Gross findings
The gross findings with liver involvement vary considerably depending on the type of lymphoma or leukemia. A subset of lymphomas and most leukemias show diffuse sinusoidal infiltration of the liver.36,37 In these cases, imaging studies commonly show hepatomegaly, but either no mass lesion or only ill-defined lesions on ultrasound and other imaging techniques. Individuals with this pattern of disease presentation also commonly have elevated liver enzymes and the biopsy can be performed to evaluate for potential causes of acute hepatitis. In contrast, mass-forming lymphomas are commonly hypoechoic on ultrasound. Computed tomography (CT) studies frequently show hypodense lesions without enhancement, mimicking carcinoma.2 Primary hepatic lymphomas can be solitary or multifocal and occasionally cystic, mimicking an abscess.2,38 On gross examination, mass-forming primary lymphomas are classically soft, gray-white to yellow, and well circumscribed (Fig. 30.7). Necrosis, hemorrhage, and cystic degeneration can also be found. The background livers tend to be noncirrhotic.
Clinical findings
The clinical findings depend in part on the type of malignancy. The term B symptoms classically refers
to drenching night sweats, fevers, and unintentional weight loss of at least 10 lbs. These systemic symptoms are generally associated with more advanced or aggressive lymphomas and are a negative prognostic finding.
to drenching night sweats, fevers, and unintentional weight loss of at least 10 lbs. These systemic symptoms are generally associated with more advanced or aggressive lymphomas and are a negative prognostic finding.
 Figure 30.7 Lymphoma, gross. This follicular lymphoma grew as a solid, white, fleshy mass. |
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.1,39 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 | |||||||||||||||||||||
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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).
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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