Lymphadenopathy with foreign-body reaction to lipids of endogenous or exogenous origins.

Foreign-body reactions to lipids, in the form of lipogranulomas or lipogranulomatosis, may involve lymph nodes and sometimes other components of the reticuloendothelial system (bone marrow, liver, spleen). They are a relatively common finding in patients who are elderly or obese, and in those with diabetes mellitus or hyperlipidemia (1,2). Long-term total parenteral nutrition can lead to massive splenomegaly, hepatomegaly, and lymphadenopathy as the lipid component accumulates in macrophages (3). Lipogranulomas may develop in lymph nodes draining the biliary system, notably the cholecystic lymph nodes, in patients with cholelithiasis, chronic cholecystitis, xanthogranulomatous cholecystitis, and other gall-bladder–related lesions. Other endogenous sources of lipids are hematomas, cholesterol deposits, xanthomatous lesions, tumors, fat emboli, and necrotic fat (4). In a patient with a 20-cm ovarian mucinous cystadenoma, periaortic and external iliac lymph nodes had numerous granulomas with multinucleated giant cells surrounding cholesterol clefts. The cyst fluid of the ovarian tumor had high concentrations of protein and lipid in the form of free cholesterol and phospholipid (5). Exogenous lipids may be inhaled and cause lipoid pneumonia; other sources of exogenous lipids are contrast media used in lymphangiography or bronchography, lipid-based substances injected into hemorrhoids, and oils used as depot vehicles to allow the slow release of injected drugs (2). Paraffin-based emollients are widely used in dermatologic practice and are usually not absorbed; however, a reversible lymphadenopathy with oleogranulomas was reported in the context of treatment of damaged skin (6).

When lymphangiography was introduced in 1952, enabling radiologic visualization of the lymphatics, a water-soluble contrast medium was initially used; this was subsequently replaced by low-viscosity iodized oil contrast media such as lipiodol, Ethiodol, and others (7). Angiographic media usually contain organic iodine and an oil base, such as that derived from ethyl esters of poppy-seed oil that is a component of Ethiodol, a substance more fluid than lipiodol (8). Ordinarily, 4 to 15 mL of contrast medium may be injected into an adult, depending on the site under investigation. A total of 15 mL is sufficient to show the lymphatics of both legs and fill the sinuses of inguinal, iliac, and periaortic lymph nodes (7). The medium is retained in the lymph nodes for a period of a few weeks to several months, and traces have been found as much as 4 years later (7). The cellular reaction in draining lymph nodes is essentially directed against the oily vehicle and, in this sense, lymphangiography-associated lymphadenopathy is in fact a lipid lymphadenopathy. Lymphangiography was formerly used to a large extent in the staging of Hodgkin lymphoma, a practice that has been gradually abandoned as radiation and chemotherapy have become more effective.

The lipids that drain with lymph into the lymph nodes are seen more frequently in the subcapsular and medullary sinuses. Lipid granulomas are formed by the accumulation of histiocytes and multinucleated giant cells around the globules of fat, which may be confluent, forming microcysts or small, empty-looking vacuoles (Figs. 50.1,50.2,50.3,50.4). Phagocytosed inside the macrophages, the lipid vacuoles are always smaller than the single vacuole of normal fat cells (4). In frozen sections, the fatty globules can be revealed by Sudan black or scarlet red stainings. In paraffin sections, the fat has been dissolved by the xylene treatment and appears as empty spaces. Such spaces, microcysts, and vacuoles are lined by fine cytoplasmic films of giant cells that stretch to encircle the foreign body. Epithelioid cells are part of the reaction, but they do not form well-defined granulomas. The multinucleated giant cells are of foreign-body type (Fig. 50.2). Lymphocytes, plasma cells, and sometimes eosinophils may accompany the cellular proliferation. Follicles with germinal centers may react to the foreign material (Fig. 50.4). Eventually, sometimes in days or weeks, but at other times in months or years, the exogenous fat is removed (2,6). In hyperlipidemia, the lipid granulomas consist of foamy cells and Touton-type giant cells. Foamy cells are also part of the process in some infectious diseases (e.g., Whipple disease, leishmaniasis), storage diseases (e.g., Niemann-Pick, Gaucher, or Fabry diseases), and diseases of unknown cause (e.g., histiocytosis X, Hand-Schüller-Christian disease).