The histopathological triad of florid reactive follicular hyperplasia, clusters of epithelioid histiocytes, and focal sinusoidal distension by monocytoid B cells has been considered to be diagnostic of toxoplasmic lymphadenitis.2,3,5
According to our study, although highly specific (96.6%), this triad had a sensitivity of only 44.4%. The limiting factor is the presence of monocytoid B cells, which were seen in only four of the nine cases of toxoplasmosis. The sensitivity of the triad was 62.5% and the specificity was 91.3% in another study, which used polymerase chain reaction as the reference standard.5
However, this is not strictly comparable with our study because of the different reference standards used. Polymerase chain reaction as a reference standard for acute toxoplasmic lymphadenitis has the problem of being oversensitive because it may pick up past infections. IgM ELISA is usually positive in all patients in the first three months,7
but may also be problematic on occasion because high antibody titres can persist for long periods.8
We tried to minimise this by limiting our subject selection to lymphadenopathy of less than six months duration.
“The most important component of our composite criterion is the presence of microgranulomas, which we defined as collections of epithelioid cells with less than 25 nuclei”
The composite criterion that we propose has a sensitivity of 100%, specificity of 96.6%, and a positive likelihood ratio of 29. The post-test probability is 0.82, up from a pre-test probability (prevalence) of 0.13.
Take home messages
- We have devised a composite criterion—(1) presence of microgranulomas, (2) lower than grade 2 macrogranuloma, (3) absence of giant cells, and (4) follicular hyperplasia—that can diagnose toxoplasmic lymphadenitis with a high degree of sensitivity (100%), specificity (96.6%), and positive likelihood ratio (29)
- These criteria should be tested further in prospective studies
The most important component of our composite criterion is the presence of microgranulomas, which we defined as collections of epithelioid cells with less than 25 nuclei. Larger collections, which we called macrogranulomas, are either absent or if present only of grade 1 (less than three/section, never containing more than 50 cell nuclei, and never having caseation). Defined thus, grade 1 macrogranulomas are probably the result of coalescence of occasional microgranulomas. Among other significant discriminators between cases and controls, paracortical widening and hyperplasia have lower specificity and sensitivity, respectively. Moreover, these are relatively subjective and liable to interobserver variation. Follicular hyperplasia with prominent germinal centres was included in the criterion primarily for differentiation from lymphomas, which sometimes show a microgranulomatous reaction.9
However, it should be remembered that interfollicular Hodgkin disease and rare cases of mucosa associated lymphoid tissue lymphoma can have a combination of reactive follicles and epithelioid clusters.
The occurrence of epithelioid cells within germinal centres, which is thought to be a specific feature of toxoplasmosis,9
was not found to have significance in our study. It was seen in two cases of toxoplasmosis and in an IgM negative case (probably tuberculosis). Although our sample included five cases of Kikuchi disease, none of them tested positive for IgM toxoplasma antibody, unlike the case reports by Kikuchi et al.10
There were two cases that showed all the features of toxoplasma lymphadenitis according to our combined criterion, but were negative for IgM. These could be patients recovering from acute infection or true negatives with as yet undetermined causes. Epithelioid cell clusters and monocytoid B cells can occur in cases of cat scratch disease, sometimes in the absence of abscesses, and such cases can be confused with toxoplasmosis.11
In conclusion, toxoplasmic lymphadenitis can be diagnosed with a high degree of confidence using the specific histopathological criteria that we have laid down. These criteria should be tested further in prospective studies.