Hepatic Granulomas: Differential Diagnosis

Epithelioid Granulomas

These are focal collections of specialized histiocytes, known as epithelioid cells, which have mainly secretory (not phagocytic) activity, a phenotypic modulation which occurs in response to antigenic stimulation. Epithelioid cells are distinguished from regular macrophages by their abundant homogeneous cytoplasm, which is free of ingested particulate matter, and their elongated curved nuclei, which are frequently located at the periphery of the cell ( Fig. 19.1 and eSlide 19.1 ). Multinucleated giant cells, lymphocytes, other inflammatory cells, and fibroblasts may be seen in and around the groups of epithelioid cells; inclusions such as asteroid and Schaumann bodies may also be present ( Fig. 19.4 ).

Necrosis is a common finding in epithelioid granulomas and different types of necrosis can be identified. The most well-recognized is caseous necrosis ( Figs. 19.5A–B ), which is very typical of tuberculosis; caseous necrosis can, however, also be seen in histoplasmosis and other fungal infections as well as occasionally in other diseases such as sarcoidosis. Histologically, caseous necrosis appears as eosinophilic, granular, acellular material characterized by complete loss of tissue structure, in contrast with coagulative necrosis, which preserves some ghost tissue outline ( eSlide 19.2 ). Granulomas with fibrinoid necrosis are typical of rheumatoid arthritis ( Fig. 19.5C ), whereas suppurative necrosis is indicative of Yersinia infection and candidiasis. Granulomas with a prominent infiltrate of eosinophils are frequently associated with parasites and less frequently with drugs.

Suppurative Granulomas (Granulomas with Central Microabscess)

This is an uncommon granulomatous inflammation pattern, characterized by a central abscess surrounded by a rim of epithelioid or foamy histiocytes. Fungi, including Candida sp. and Histoplasma sp., but also actinomycosis and Nocardia infections, are associated with this type of inflammation. Sometimes, especially if some degree of immunosuppression is present, the reaction is more diffuse, with smaller focus of suppurative inflammation interspersed with a histiocytic reaction.

Microgranulomas

These are minute collections of typically three to seven macrophages within the hepatic lobule ( Fig. 19.6 ). They are often admixed with other inflammatory cells, mainly lymphocytes, or associated with apoptotic hepatocytes (see Fig. 19.6 , inset). Hemosiderin or ceroid pigment may be present. Microgranulomas are generally seen in any chronic inflammatory disease of the liver as a nonspecific change to cellular injury and hepatocyte necrosis and do not have any specific diagnostic connotation. They therefore need to be distinguished from epithelioid granulomas, which have distinct diagnostic significance. An important exception is the nodular form of leishmaniasis ( eSlide 19.3 ), which may demonstrate numerous very small epithelioid granulomas ( Fig. 19.7 ).

Lipogranulomas

These are focal, loose collections of macrophages or epithelioid cells surrounding single or multiple droplets of neutral lipid. When neutral fat escapes the confines of the hepatocyte cell membrane and enters the extracellular compartment, histiocytes settle around it, and a lipogranuloma is formed. Ultrastructurally, remnants of the liver cell may be seen between the fat droplet and the histiocytes. Some of these macrophages can adopt a foamy appearance and lymphocytes and plasma cells may be interspersed between them. They are often associated with a little fibrous tissue ( Fig. 19.8A–B ). Lipogranulomas are characteristically found in zone 3, in the vicinity of the central vein, and are most often seen in fatty livers, as part of nonalcoholic fatty liver disease and, even more frequently, in alcoholic liver disease. Lipogranulomas have been associated with the ingestion of mineral oil; these are morphologically similar to those associated with fatty livers. Aside from rare exceptions, lipogranulomas are not believed to progress and are therefore not clinically significant. In addition to the liver, they may also be found in the spleen, lymph nodes, and lungs.

Foamy Macrophage Aggregates

This pattern is associated with infections, mostly in immunocompromised patients. Besides foamy cells, there is very little additional inflammatory response. The most commonly implicated microorganisms are atypical mycobacteria in patients with acquired immunodeficiency syndrome and some fungi such as Cryptococcus ( Fig. 19.9 ).

Fibrin-Ring Granulomas

The fibrin-ring or doughnut granuloma is a very unusual but distinctive type of granuloma first described in Q-fever. It is characterized by a ring of fibrin around a central core of fat, both of which are surrounded by epithelioid cells or neutrophils; the fibrin may not always form a complete ring. Besides Q-fever, other causes of hepatic fibrin-ring granulomas include infectious agents such as cytomegalovirus, Epstein-Barr virus (EBV), hepatitis A virus, hepatitis C virus, and leishmaniasis. Noninfectious causes include hypersensitivity to medication (mainly allopurinol ), malignancy (eg, Hodgkin and non-Hodgkin lymphoma ) and, exceptionally, giant cell arteritis. Infections are the most common causes of fibrin-ring granulomas; therefore, differential diagnosis hinges on serologic tests. However, associated histopathologic features may help in the differential diagnosis; the presence of eosinophils may suggest a possible drug reaction whereas sinusoidal lymphocytosis raises the possibility of EBV infection. The pathogenesis of the fibrin-ring is not clear, but injury to sinusoidal endothelium might be an important factor.

Tuberculosis

Although common in both patients with pulmonary and extrapulmonary tuberculosis (TB), liver involvement by tuberculosis is usually clinically silent; only occasional cases show local signs and symptoms of hepatic involvement, or constitute the initial or sole presenting feature of the disease. A miliary pattern is the most common form and is said to occur in 50% to 80% of all patients dying of pulmonary tuberculosis. An extensive review of the world literature in 1952 documented only 80 cases of hepatic tuberculosis with large abscesses and nodules or tuberculomas and classified tuberculosis of the liver into miliary tuberculosis (part of generalized disease) and localized disease, which could be further divided into focal or nodular tuberculosis (including hepatic abscess or tuberculomas) and into the tubular form (intrahepatic duct involvement). Since then, isolated case reports or case series of localized hepatic tuberculosis appear in literature, with varied nomenclature ranging from tuberculous liver abscess to tuberculous pseudo-tumor , primary hepatic tuberculosis , tuberculous hepatitis , tuberculous cholangitis, and tuberculosis of the bile duct , generating some confusion in classification and clinical significance of this disease.

A useful classification of hepatic tuberculosis was proposed by Alvarez in 1998 :

• 1.

  Miliary tuberculosis, consisting of hepatic involvement as part of generalized miliary TB, usually with no signs or symptoms relevant to the liver.

• 2.

  Tuberculous hepatitis, which presents with unexplained fever, with or without mild jaundice and hepatomegaly, caseating or noncaseating granulomas on liver biopsy and improvement with antituberculous therapy.

• 3.

  Hepatobiliary tuberculosis, presenting with signs and symptoms relevant to the hepatobiliary tract and including two subtypes: the first without bile duct involvement, presenting as solitary or multiple nodules, tuberculomas and tuberculous hepatic abscesses; and the second with bile duct involvement causing obstructive jaundice, either because of enlarged nodes surrounding the bile ducts or granulomatous involvement of the ductal wall producing inflammatory strictures. Mass forming primary hepatic tuberculosis that mimics intrahepatic carcinoma or hilar cholangiocarcinoma presents a significant clinical problem that requires a liver biopsy to reach the correct diagnosis.