Although lymphadenopathy is a common manifestation and one of the diagnostic criteria of AOSD, there are only a few sporadic reports about lymph node pathology in AOSD. This might be because of the difficulty in recognising the pathological characteristics of biopsy specimens encountered only occasionally by pathologists. In addition, the clinical features of AOSD, which include fever, hepatosplenomegaly, skin rash, and polyclonal hypergammopathy, can mimic malignant lymphoma, so that understanding the lymph node pathology of AOSD is very important. AOSD lymphadenopathy has been described simply as “reactive hyperplasia, frequently with accompanying histiocytosis”, “plasma cells and polymorphonuclear cell infiltrates with sign of reactive hyperplasia”, “the follicular pattern of reactive hyperplasia”, or “atypical paracortical hyperplasia”.1,2,6,12
Through a literature review and the analysis of our 12 cases, including the one with an additional follow up biopsy, we conclude that AOSD lymphadenopathy represents a wide spectrum of histopathological features showing dynamic changes. Basically, lymphadenopathy is characterised by paracortical hyperplasia with vascular proliferation. Other reports regarding AOSD as one of the causes of florid reactive follicular hyperplasia have also been found.12,13
The follicular hyperplasia pattern was seen in two of our patients, and interestingly, the lymph node of patient 12 in our series showed a follicular hyperplasia pattern in the initial biopsy and atypical paracortical hyperplasia in the follow up biopsy. This might explain, in part, the various pathological descriptions of AOSD lymphadenopathy.
The widened paracortical area was infiltrated by variable numbers of atypical B and T immunoblasts, and the extent of the immunoblastic reaction determined the difficulty of the differential diagnosis from malignant lymphoma. In extreme cases, classified as exuberant immunoblastic reaction pattern, portions or entire areas of the lymph node were effaced by actively proliferating large T immunoblasts. In such cases, detailed evaluation of clinical and laboratory findings, and additional studies such as immunohistochemistry and TCRγ gene rearrangement are mandatory. Unlike angioimmunoblastic T cell lymphoma, clear cell clusters, CD21 positive follicular dendritic cell proliferation in the extragerminal centre area, and EBER positive large B immunoblasts were not found in AOSD. In addition, in contrast to angioimmunoblastic T cell lymphoma, AOSD occurs mainly in young adults. And unlike peripheral T cell lymphoma, there was no distinct cellular atypism, and no clonal TCRγ gene rearrangement. Mitotic activity was not increased in the small to medium sized T cells. Kojima et al
also reported that the CD4 : CD8 positive cell ratio is about 3 : 2 and cytotoxic T cells are seen in AOSD. However, in nodal peripheral T cell lymphoma, most T cells are CD4 positive.8
“The lymph node of patient 12 in our series showed a follicular hyperplasia pattern in the initial biopsy and atypical paracortical hyperplasia in the follow up biopsy”
We could find no associations between the clinical features and lymph node patterns in AOSD. Although two of the three patients with an exuberant immunoblastic reaction were complicated by either respiratory distress or endocrinopathy, whether the degree of immunoblastic reaction might reflect the disease activity is not certain. Two patients with pronounced S-100 positive histiocytosis in the lymph node pathology showed raised serum ferritin values—from 70 to 100 times the normal value. One of them showed the feature of haemophagocytic syndrome on bone marrow examination. These findings are in accordance with the suggestion by Coffernils et al
that the very high serum ferritin concentrations encountered in AOSD reflect the presence of histiocytic hyperactivity, which sometimes leads to a haemophagocytic syndrome.14
The pathogenesis of AOSD is unclear. An abnormal immune reaction to an infectious agent such as a virus has been suggested, although no such organism has been identified, and an imbalance of cytokines has also been proposed.15
Abnormal immune reactions can provoke various reactive lymphadenopathies and malignant lymphoma. In fact, there are several reports of AOSD accompanied by Kikuchi’s disease, Castleman’s disease, and malignant B cell lymphoma.15–19
A study done by Quaini et al
showed that AOSD lymphadenopathy is a process involved by mixed B and T cells,7
and the dynamic change of lymph node pathology from follicular to paracortical hyperplasia in our study could also support their hypothesis. However, the facts that the major histological pattern of AOSD lymphadenopathy is atypical paracortical hyperplasia, and that the exuberant immunoblastic reaction frequently mimics malignant T cell lymphoma, suggest that the T cell mediated immune reaction may play an important role in the course of disease.
Take home messages
- The lymph nodes of adult onset Still’s disease (AOSD) exhibit a wide spectrum of histopathological features, which can be classified into four patterns: atypical paracortical hyperplasia, burnt out histiocytic reaction, exuberant immunoblastic reaction, and follicular hyperplasia
- The histopathology of the lymph nodes can change dynamically during the course of disease
- Combining immunohistochemical and genetic studies with careful evaluation of clinical and laboratory findings would make diagnosis more accurate
- Understanding the nature of AOSD lymphadenopathy could also help to elucidate the pathogenesis of the disease
In conclusion, our report emphasises that the lymph nodes in AOSD exhibit a wide spectrum of pathohistological features, which can be classified into four patterns, and that the pathology can change dynamically during the course of disease. Although there was no definite association between lymph node pathology and clinical features, future studies may reveal such an association. Combining immunohistochemical and genetic studies with careful evaluation of clinical and laboratory findings would prevent the overdiagnosis and underdiagnosis of the lymph node specimen. Understanding the nature of AOSD lymphadenopathy could also help to elucidate the pathogenesis of the disease.