Definition
A number of entities, other than lymphomas and metastatic tumors, cause enlargement of the cervical lymph nodes. In a series of articles, we will discuss some of these entities, starting with toxoplasmosis.
Toxoplasmosis is the general term for infection and disease in man and animals caused by the parasitic protozoan Toxoplasma gondii. Animals affected include cattle, poultry, sheep, goats, cats, various other animals kept as pets, and various captive zoo and wild animals. In humans, the result of infection may range from asymptomatic to severe disease. Asymptomatic infection occurs both congenitally and by ingestion of infected material in immunocompetent individuals. [1, 2, 3] In immunocompetent patients, toxoplasmosis lymphadenitis is self-limited. If lymphadenitis or symptoms are severe or persistent, the standard treatment is a combination of pyrimethamine and sulfonamides. [4] In congenital infection and immunosuppressed individuals, more severe forms of the disease may occur. [1, 5, 6, 7]
Lymphadenitis is the most common clinical form of the disease, [1, 5, 6, 8] with 3-7% causing clinically significant lymphadenopathy, [9] particularly cervical lymphadenopathy. Thus, recognition of toxoplasmosis lymphadenitis is important (see the image below for an example). The bulk of this discussion will be on the features of toxoplasmosis lymphadenopathy.
Epidemiology
T gondii infection in humans is widespread, although its prevalence as determined by serology shows regional variability. [10, 11] Jones et al tested sera of 27,145 persons aged 12 years and older. Age-adjusted seroprevalence was higher in the Northeast (29.2%) than in the South (22.8%), Midwest (20.5%), or West (17.5%) (p < 0.05). Only approximately 1% of seropositive individuals will experience signs or symptoms of toxoplasmosis disease. [11]
The Centers for Disease Control and Prevention estimates that 11% of the United States population 6 years and older have been infected with T gondii. [3] The highest recorded seroprevalence rate was 93% among Parisian women who consume raw and undercooked meat. [10] However, rates have declined in the last 2 decades. [12]
Etiology
The etiologic agent of toxoplasmosis, the parasite T gondii, is a sporozoan of the coccidian group. Infection by this parasite is inextricably tied to its complex life cycle. A number of mammals are subject to infection and act as intermediate hosts, although domestic cats and other felines are the only definitive host. [13]
Life cycle of T gondii
Tachyzoites emerge in a stage in the life cycle and rapidly multiply by asexual means in cells of intermediate hosts and in nonintestinal cells of the definitive host. Cells that can no longer sustain the rapidly growing tachyzoites burst. [14] In healthy individuals, an appropriate immune response controls the rapid proliferation of the parasite. However, in another stage, by mechanisms that are not fully understood, a portion of the tachyzoites transform into the slowly proliferating bradyzoites. Eventually, the bradyzoites become surrounded by a dense wall; the resulting structure is referred to as a tissue cyst. These tissue cysts may arise in visceral organs (eg, lungs, liver, and kidneys), but they are more commonly found in neural and muscular tissues, such as the brain, eyes, and skeletal and cardiac muscle.
Bradyzoites in tissue cysts are resistant to the immune system and to the drugs that are commonly used to treat toxoplasmosis. Protection of bradyzoites from the immune system abrogates the inflammatory response and, thus, any pathologic damage caused by the presence of tissue cysts. [5, 15] In cats, bradyzoites released from ingested tissue cysts penetrate small intestinal epithelial cells. Once inside these cells, there are multiple stages of asexual and sexual development that result in the formation of sporulated oocysts, which contain sporozoites. [14] Oocysts are released into the intestinal lumen of the cat when infected epithelial cells burst. [16] Dissemination of tachyzoites to other organs in the body occurs via the blood and lymphatics [5] and infected macrophages. [17]
There are several routes for human infection by T gondii, such as ingestion of material contaminated by oocyst-containing cat feces or ingestion of improperly prepared meat containing tissue cysts. Once ingested, the action of intestinal enzymes results in the release of sporozoites from oocysts or bradyzoites from tissue cysts. Released sporozoites or bradyzoites penetrate cells, transform into tachyzoites, and proliferate. [5] In pregnant women, tachyzoites are capable of crossing the placenta, [17] resulting in focal placental lesions. [6] Infection of the placenta may then result in infection of the fetus. [6]
Finally, it appears that in certain circumstances, tissue cysts may rupture, releasing bradyzoites that reactivate infection. [1, 6]
Location
Lymphadenopathy caused by toxoplasmosis usually occurs in the head and neck region, with the cervical nodes most often affected; supraclavicular, inguinal, mediastinal, axillary, and mammary lymph nodes may also be involved. [8, 18, 19, 4] A minority of infected patients will have generalized lymphadenopathy. [4]
Clinical Features and Imaging
Most immunocompetent people infected with T gondii are asymptomatic. [1, 6] When clinical manifestations occur, they are generally mild. Lymphadenitis is the most common clinical form of toxoplasmosis and may be accompanied by a number of nonspecific symptoms in a portion of individuals with lymphadenopathy, such headache, fever, malaise, fatigue, sore throat, and myalgia. [1, 5, 6, 4] At the sites of lymphadenopathy, there may be single or multiple nonmatted lymph nodes that are generally not tender; firmness of the lymph nodes is variable. Most lymph nodes are less than 3 cm in diameter. [18]
Systemically, in the more severe cases, pulmonary necrosis, myocarditis, hepatitis, and retinochoroiditis, among other entities, may occur. [1, 5] The most severe forms of toxoplasmosis occur in individuals with human immunodeficiency virus infection (HIV)/acquired immunodeficiency syndrome (AIDS) or in those who are otherwise immunocompromised due to immunosuppressive therapy received for malignancy or organ transplantation. [1, 6, 2, 3]
The risk of congenital toxoplasmosis infection is lowest in the first trimester of pregnancy and highest in the last trimester, although the disease is more clinically severe if infection occurs in the first trimester. [1] The results of congenital toxoplasmosis are variable, including spontaneous abortion and stillbirth. Classic signs of congenital toxoplasmosis in live-born infants include hydrocephalus or microcephalus, cerebral calcifications, and retinochoroiditis. [1] Ocular disease is the most common manifestation of congenital toxoplasmosis, and retinochoroiditis may occur later in life in an otherwise healthy child who was exposed to T gondii in utero. [1, 6, 20, 21]
A study reported that toxoplasma seropositivity was high in patients with cirrhosis. The authors added that these results suggested that cirrhotic patients may be considered a toxoplasmosis risk group. [22]
Gross Findings
Most lymph nodes involved by toxoplasmosis lymphadenitis are less than 3 cm in diameter. [18] Cut sections of biopsied lymph nodes are firm, white, and may have a suggestion of follicular hyperplasia. [23]
Microscopic Findings
The classic constellation of features that characterize toxoplasmosis lymphadenitis was noted in the 1940s, although recognition of T gondii as the etiologic agent and its publication in the Scandinavian literature did not occur until 1950. [24] This constellation of microscopic findings, commonly referred to as the "toxoplasmosis triad" includes follicular hyperplasia, the presence of monocytoid cells in subcapsular and trabecular sinuses, and the presence of clusters of epithelioid histiocytes (see the following images). [24]
The follicular hyperplasia in toxoplasmosis lymphadenitis has been described as "striking" [23] and "florid." [25] The follicles are large and irregularly shaped, and the germinal centers have a relative lack of clear definition and contain numerous centroblasts and mitotic figures. There is abundant cell necrosis with associated karyorrhectic debris both inside and outside of tingible body macrophages (see the images below). [18, 23, 24, 26]
The prominent cells present in the subcapsular and trabecular sinuses were initially described as "monocytoid" [18] or "macrophages" [23] that have an abundant clear [26] or amphophilic [23] cytoplasm and large round nuclei, which are also variably described as being round to indented [26] or contorted. [23] Immunohistochemical studies have demonstrated that these "monocytoid" cells are in fact B cells [27, 7] (see the following image); they are now usually referred to as monocytoid B cells.
The clusters of epithelioid histiocytes are relatively small and present in paracortical regions as well as in follicular regions, including within the germinal centers (see the image below). [18, 23, 24, 26] These epithelioid histiocytes are described as having abundant eosinophilic cytoplasm and vesicular nuclei. [23, 24]
Several other histopathologic features merit mention. Toxoplasmosis lymphadenitis has been mistaken for Hodgkin lymphoma, both the lymphocyte predominant and nodular sclerosis types, and atypical lymphoid hyperplasia. The confusion arises from the fact that clusters of epithelioid histiocytes may be present in lymph nodes involved by Hodgkin lymphoma and atypical lymphoid hyperplasia.
There are 2 key histologic features of toxoplasmosis lymphadenitis that help to differentiate it from the above mentioned conditions: (1) The lymph node architecture of a toxoplasmosis lymph node is largely intact with relatively little effacement, in contrast to the architecture of lymph nodes involved by Hodgkin lymphoma or with atypical lymphoid hyperplasia; and (2) clusters of epithelioid histiocytes are found in germinal centers in toxoplasmosis lymphadenitis but not in the other 2 entities. [28]
The clusters of epithelioid histiocytes in toxoplasmosis lymphadenitis generally contain less than 25 nuclei. [25] Larger clusters, the presence of multinucleated giant cells, and caseation are unusual in toxoplasmosis lymphadenitis and should bring to mind other diagnoses, such as sarcoidosis or tuberculosis. Additionally, florid follicular hyperplasia is not typical of sarcoidosis. [23, 24, 29]
The differential diagnosis for toxoplasmosis lymphadenitis is very large (see Differentials), because the disease has very nonspecific, if any, symptoms. However, the diagnosis may well be suggested by the histomorphology of a biopsied lymph node. Several groups have attempted to determine the value of the toxoplasmosis triad in making the diagnosis by determining whether the results of serology studies correlate with the presence or absence of the triad. Such studies included the toxoplasma immunoglobulin (Ig) M serology, the Sabin-Feldman dye test (which determines if toxoplasma IgA, IgG, and IgM antibodies are present), [30] and complement fixation titers.
In 3 studies, there was good correlation between the presence of the toxoplasmosis triad and positive serologic results in patients: 97%, [24] 85%, [18] and 95%. [26] respectively. In another study that correlated histologic findings with serology, the sensitivity of the triad was determined to be 97% and the specificity was 80%. [29] However, a similar study showed a high specificity of 96.6% but a lower sensitivity of 44.4%. [25] Another study that correlated the toxoplasmosis triad with the presence of T gondii DNA as determined by polymerase chain reaction (PCR) also showed similar results: 91.3% specificity and 62.5% sensitivity. [31]
Thus, the evidence indicates that recognition of the typical histologic features of toxoplasmosis together with appropriate serologic studies will lead to a reasonably confident diagnosis of toxoplasmosis.
Immunohistochemistry
Reagent T gondii antibodies for use in immunohistochemistry are available, and T gondii forms have been identified with immunohistochemistry in formalin-fixed sections of lymph nodes from patients with toxoplasmosis. [32] However, use of immunohistochemistry does not figure prominently in the literature describing toxoplasmosis lymph nodes. Indeed, in conventionally fixed and stained tissue sections, cyst forms [23, 33] and other T gondii forms [18, 19, 34] are infrequently identified.
T gondii forms have been readily isolated by intraperitoneal inoculation of toxoplasmosis lymph node samples [19] as well as by polymerase chain reaction (PCR) from such samples. [31] However, the sensitivity of these methods for detection of the organism may belie the actual number of parasitic forms in a toxoplasmosis lymph node — an apparently less sensitive PCR method infrequently detected T gondii DNA from infected lymph nodes. [35]
It has been suggested that the reactive changes seen in toxoplasmosis lymph nodes may be a reaction to T gondii products rather to forms of the organism itself. [36] In any event, recognition of the classic histologic features and serology appears to render the use of immunohistochemistry in the diagnosis of toxoplasmosis lymphadenitis somewhat superfluous.
Differential Diagnosis
Collagen Vascular Disease
Dermatopathic Lymphadenitis
Fungal Infection
Local Infection
Medication Reaction
Metastatic Tumor
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Toxoplasmosis Pathology. This low-power photomicrograph shows the large, irregularly shaped germinal centers and clusters of epithelioid histiocytes found in toxoplasmosis lymphadenitis.
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Toxoplasmosis Pathology. This photomicrograph shows karyorrhectic debris inside a germinal center.
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Toxoplasmosis Pathology. This photomicrograph shows karyorrhectic debris within a tingible body macrophage inside a germinal center.
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Toxoplasmosis Pathology. This photomicrograph shows the "monocytoid" cells that are actually B cells.
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Toxoplasmosis Pathology. This photomicrograph shows the "monocytoid" cells stained for CD20, a specific B-cell antigen.
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Toxoplasmosis Pathology. This photomicrograph shows a cluster of epithelioid histiocytes.
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Toxoplasmosis Pathology. This photomicrograph shows clusters of epithelioid histiocytes within a germinal center.
