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Kikuchi Disease

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Published: December 2012

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Kikuchi disease is rare and usually self-limiting. However, accurate diagnosis is essential to avoid treatments that could have deleterious effects on the patient. In this case study, Dr. Jevremovic walks you through the various stains and tests needed to identify this disease.

Presenter: Dragan Jevremovic, MD, PhD

  • Assistant Professor of Laboratory Medicine and Pathology at Mayo Clinic
  • Co-Director of the Cell Kinetics Laboratory in the Division of Hematopathology at Mayo Clinic in Rochester, Minnesota

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This case is about a 27-year-old female who presented with 1 week history of fever and left cervical lymphadenopathy. The chest X-ray and the CBC were unremarkable, as was the peripheral blood flow cytometry finding, which showed no monotypic B-cells, no aberrant T cells, and no increase in blasts. The clinicians tried NSAIDS and antibiotic therapy for 1 week and that was unsuccessful, so the patient underwent a lymph node biopsy.

In this slide you can see the low power of H&E stain of the lymph node, which shows that the architecture of the lymph node is partially effaced by the areas of confluent necrosis.

On a medium magnification, you can see that necrotic areas contain numerous large atypical cells. The surrounding areas show somewhat moth-eaten appearance with scattered large cells.

Necrotic areas were sharply demarcated and you could also start to appreciate that there is some apoptotic debris.

On high magnification, necrotic areas show that there is prominent apoptotic necrosis with numerous apoptotic bodies and debris. Histiocytes were also prominent in the necrotic areas, but there were no neutrophils present.

Immunohistochemically we did several stains, CD3 stain showed that there is a prominent T-cell paracortical hyperplasia and also that some of the large cells with in the necrotic areas and around them are indeed T-cells.

CD20 stain shows remnants of primary follicles and relative paucity of B cells outside the follicles.

PAX-5, another B-cell marker, matches CD20 stain, suggesting that large atypical cells that are present are not of B-cell lineage.

CD30 stain showed only weak staining of activated immunoblasts. No large atypical cells were present on CD30 stain.

CD68 stain is the marker for histiocytes and it showed that the majority of cells within necrotic areas were of histiocytic lineage and they were mixed with the previously shown T cells.

CD123 highlights that the cells in the necrotic area are in fact plasmacytoid dendritic cells.

EBV, (Epstein-Barr virus) in situ hybridization was negative.

This constellation of morphologic and immunophenotypic features led us to the diagnosis of Kikuchi disease.

Kikuchi disease, also known as Kikuchi- Fujimoto disease, pathohistologically is histolytic necrotizing lymphadenitis. It is a rare, self-limiting disease, seen much more frequently in females then males and more common in Asian population. However, you should keep in mind that about 75% of all US cases are seen in Caucasians. Etiology or pathogenesis of Kikuchi-Fujimoto disease is still uncertain. Multiple micro organisms have been proposed as potential causes. These include viruses, as well as bacteria and parasites, and all of these have in common, to induce secretion of interferon gamma, which is thought to play a role in pathogenesis. However, none of these have been confirmed to be a cause of Kikuchi disease. Also, some authors describe autoimmune reactions as a cause for Kikuchi disease and, actually, sex and age of patients with Kikuchi disease is very similar to those that are affected by systemic lupus erythematosus. Other cytokines that have been reported pathogenesis include interleukin 6 and interferon gamma.

Clinically, patients with Kikuchi disease present with fever and lymphadenopathy. Fever is often accompanied by leukopenia and rarely other symptoms such as fatigue, rash, splenomegaly, arthritis, and, very rarely, aseptic meningitis. Lymphadenopathy is most commonly cervical, especially posterior, but sometimes can involve other lymph node groups. Very rarely there is extranodal involvement by Kikuchi disease.

Histopathologically there are 2 different phases that can be seen in patients with Kikuchi lymphadenopathy. In the proliferative phase, there is follicular hyperplasia as well as paracortical immunoblasts, histiocytes, and plasmacytoid dendritic cells. There is also apoptotic background, but these patients do not have areas of necrosis, as seen in the current patient. Necrotizing phase is the phase that is most commonly seen usually because patients do not get a lymph node biopsy until the phase of necrosis, which usually shows partial effacement of the lymph node by patchy areas of confluent necrosis as seen in this case. Non-necrotic areas have preserved architecture. There is a marked histiocytic infiltrate as well as numerous activated lymphocytes, apoptosis, and karyorrhexis. Plasmacytic dendritic cells and thrombosed vessels can be seen in the periphery of necrotic areas.

This is a picture of the proliferative phase with scattered activated immunoblasts and the numerous small lymphocytes as well as some apoptotic debris. This picture can often be seen in a viral lymphadenitis cases such as Epstein-Barr virus infection.

Necrotic phase, such as this case, shows sharply demarcated areas of confluent necrosis.

Differential diagnosis includes several entities, most important of which is probably high-grade lymphoma. High-grade lymphomas show total effacement of the lymph node and immunohistochemically should be distinguished from cases of Kikuchi disease. CD123 would show much fewer plasmacytic dendritic cells then in Kikuchi disease.

Cases of classical Hodgkin lymphoma show large atypical cells, which are Reed-Sternberg and Hodgkin cells, as well as small reactive cells background, as well show fewer plasmacytic dendritic cells. Marginal zone lymphoma can look a lot like proliferative phase of Kikuchi- Fujimoto disease; however, in this case, the majority of the cells are small B cells and there’s also evidence of clonality either by immunohistochemistry or by molecular genetic studies.

In addition, I already mentioned that Epstein-Barr virus lymphadenitis can be necrotizing and can look a lot like Kikuchi disease. Viral studies have to be performed sometimes to distinguish these disorders. Other virus that can mimic Kikuchi disease is herpes simplex virus lymphadenitis, but this form of lymphadenitis usually presents with numerous neutrophils as well as viral inclusions. Systemic lupus erythematosus lymphadenitis can have a very much over lapping histology with Kikuchi disease. Neutrophils and plasma cells are more common, but some authors consider the distinction between Kikuchi and systemic lupus erythematosus lymphadenitis cannot be adequately made based on only lymph node morphology, and that clinical correlation is necessary for distinguishing these 2 disorders. Necrotizing granulomas, such as in cases with tuberculosis or histoplasmosis or cat scratch fever, are characterized by numerous epithelioid granulomas and special stains that can show the presence of microorganisms. Finally, lymph node infarction can be confused with Kikuchi disease. However, lymph node infarction shows no nuclear debris and usually involves the majority of the lymph node, sparing only a narrow capsular rim.

There is no available treatment for Kikuchi disease. However, it is usually a self-resolving disorder, which disappears in several months. For severe or persistent cases, clinicians do use steroids for treatment to alleviate symptoms. A small proportion of patients develop systemic lupus erythematosus, which underlines that these 2 disorders fall in the same spectrum.

In summary, Kikuchi disease is a rare, self-limiting disease that is presenting with fever and lymphadenopathy. Morphologically, it is characterized by geographic necrosis with preserved architecture in non-necrotic areas. For diagnosis, it is important to exclude infections, especially Epstein-Barr virus infection. In doubt, CD123 stain can be helpful to highlight plasmacytoid dendritic cells, which are abundant in cases of Kikuchi disease. And one advice for not getting in trouble with diagnosing Kikuchi disease is not to go too quickly on high power, because if you do that, if you miss the general architecture of the disease, you can very quickly go into wrong path in thinking you are dealing with a high-grade lymphoma.