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A Peculiar case history
Sakura is a 28-year-old woman, who initially presented to the hospital with fever for one month duration and unilateral, tender cervical lymphadenopathy. She had associated malaise, loss of weight, headache and night sweats as well. Since this presentation strongly suggested either TB or Lymphoma, relevant investigations were done for both. Investigations for TB were negative, and it was dismissed as a differential. After performing an FNAC on the enlarged lymph nodes, on the grounds of suspicion of Non-Hodgkin’s lymphoma, she was started on chemotherapy.
Sakura returns within a month, now with the adverse effects of chemotherapy in addition to her non-resolving symptoms, which has only prompted further investigation.
As the attending doctor, what will you do?
Having excluded lymphoma, we could lean towards the rare disorder known as “Kikuchi Fujimoto disease” as a possible diagnosis.
What is Kikuchi Disease?
Kikuchi-Fujimoto disease or in more technical terms histiocytic necrotizing lymphadenitis, is a rare, but benign condition of the lymph nodes. It was initially described in Japan, by two pathologists Kikuchi and Fujimoto, hence the name. It is a self-limiting condition, of which the greatest danger is in it being misdiagnosed as lymphoma, tuberculosis or SLE, which it closely mimics.
Who is Affected?
This disease is quite rare; hence the exact incidence remains unknown. The incidence of this diseases might actually be higher than reported, because it is frequently overlooked. This could be because it manifests as a common presentation (i.e, swollen lymph nodes), and since it is a self-limiting diseases. Through studies conducted so far, the affected population inclines towards females of age less than 40 years, although recent studies show that males maybe equally affected. Asian inheritance has also been shown to favor occurrence of the disease, but cases have been reported across the world. Pediatric populations too are not exempted.
What causes this?
Though the exact etiology of Kikuchi disease remains unknown, two promising theories on possible causes have been forwarded to date. They are;
- Infectious theory
- Autoimmune theory.
According to the infectious theory, either viral or bacterial organisms act as the trigger for a self-limiting autoimmune process. Suspected viral organisms include Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus type 1 and 2 (HSV 1 & 2), cytomegalovirus (CMV) and human herpes virus (HHV 6, 7, 8) to name a few. The suspected bacterial organisms include Brucella, Bartonella henselae, Yersinia enterocolitica, Entamoeba histolytica, and Mycobacteria.
However, no viruses nor bacteria have been found in biopsied tissues and cultures and hence, this theory has not yet been proven.
Coming to the autoimmune theory, scientists have found some association between some HLA subtypes (which are antigens present on the surface of all human cells) and Kikuchi disease. Interestingly, the specific HLA subtype (HLA class II – DPA 1 and 2) in question is more commonly found in the Asian population, which explains why this disease is more predominant in Asians.
It has also been found that there is a relationship between Kikuchi Fujimoto disease and other autoimmune diseases, more commonly, SLE. Others include Wegner’s granulomatosis, Sjogren’sdisease, Hashimoto’s thyroiditis and others. However, antibodies found in these diseases are usually negative in patients with Kikuchi, and even if they are found, it is questionable whether this relationship truly exists, and future research is warranted.
How would a Patient Present?
On history
A typical patient would be a female in her late twenties or early thirties. Taking a complete history is extremely important so that we do not misdiagnose her as a patient with lymphoma. She may complain of painful cervical lymphadenopathy, which is usually unilateral but may sometimes be bilateral or generalized.
Other complaints would include non-specific symptoms such as fever, fatigue, malaise, weight loss, night sweats, and headache which may easily be confused with malignancy or tuberculosis.
There may also be features favoring an upper respiratory tract infection or others which favor an autoimmune process such as arthralgia and a non-specific rash.
There may be a positive family history in some instances, but this is not always the case. Look for environmental triggers and other social factors which may have precipitated this condition.
Your Differentials
By now, it wouldn’t be surprising if one of your major differentials is Non-Hodgkin’s lymphoma. In fact, about 40% of patients with Kikuchi disease are started on chemotherapy after being frequently misdiagnosed for lymphoma.
Other than this obvious differential, here are some of the other diseases that may cross your mind:
- SLE – because of the similar rash, alopecia and arthralgia
- Tuberculosis – as they both present with fever and lymphadenopathy
And any other disease which may cause cervical lymphadenopathy such as:
- Cat-scratch disease
- Epstein-Barr virus
- Kawasaki’s disease
- Sarcoidosis
- Leprosy
- Syphilis
- Toxoplasmosis
Other than this, upper respiratory tract infections like pharyngitis and conditions like otitis media should also be considered in pediatric age groups.
On Examination
Generally, your patient will be ill looking, running a fever and may have a prominent cutaneous rash at first glance. If you take a closer look, you may notice a cervical lymphadenopathy. Usually, they are the posterior lymph nodes but there may be occasional involvement of the supraclavicular and axillary nodes. The affected nodes will be mobile, non-suppurative, solitary and tender. They may enlarge up to 7 cm in diameter although most commonly, they stay at a smaller size of 2-3 cm.
Focusing on the rash, it may be maculopapular, morbilliform or nodular in character and there may be associations with diffuse alopecia, and other dermatological conditions (like those seen in cutaneous lupus). Sometimes, mouth ulcers may also be present. Coming to the limbs, the degree of arthralgia can be determined. It is usually an asymmetric polyarthritis and very rarely there may be enthesitis and dactylitis.
On examination of the patient’s neurological system, they may have aseptic meningitis which presents as just a headache, but lacking features of neck stiffness, positive Kernig’s or Brudzinski’s sign.
It may be possible to elicit splenomegaly and hepatomegaly as well, although these are not universal findings. Multiorgan involvement doesn’t usually occur unless your patient has had a recent solid organ transplant.
What Investigations would you do?
All the investigations you order for Sakura, should be targeted at excluding the more sinister differentials, and confirming the presence of Kikuchi disease.
For biochemical tests, a full blood count is needed. This would usually show a mild granuloleucopenia or rarely agranulocytosis! Sometimes, a blood picture may show atypical lymphocytes, although this may not always be present.
Inflammatory markers like CRP, ESR and tissue ferritin may be elevated indicating the presence of an ongoing acute phase response, and in some instances, we might find an elevated LDH level, which indicates hepatic involvement.
An antibody panel is mandatory to differentiate from SLE. These include Anti-nuclear antibody (ANA), Rheumatoid factor, and Lupus erythematosus preparation.
To exclude infectious causes, serology can be done for the viral diseases we suspect, whereas a sputum culture or GeneXpert can be carried to exclude tuberculosis.
Imaging studies may be useful to confirm the type of lymphadenopathy, and CT imaging is useful to differentiate between the lymphadenopathy in TB and that in Kikuchi disease. Also, a chest x-ray is mandatory in all patients suspected with TB.
An FNAC is not helpful in distinguishing between lymphoma and Kikuchi disease as we realized with our patient, Sakura.
The definitive diagnosis is a lymph node excisional biopsy. There are some histopathological features present which differentiate Kikuchi disease from other conditions.
Histologically, there are three phases to the disease. There are a lot of pathological terms coming up, but don’t let these scare you! This is mostly up to the pathologists to determine and give a verdict.
- The proliferative phase – Here we can see follicular hyperplasia with infiltrates of histiocytes (which have crescent-shaped nuclei) and lymphocytes, but an absence of neutrophils and eosinophils.
- The necrotizing phase – This shows extensive breakdown of histiocyte nuclei, which is known as karyorrhexis as well as many necrotic foci. There is a discrepancy about whether the normal lymph node architecture is disrupted or not.
- Xanthomatous phase – Foamy histiocytes can be seen with resolution of necrosis.
Other histopathological findings which may be important in differentiating between Kikuchi disease and malignant lymphoma include the absence of Reed-Sternberg cells, a relatively low mitotic rate and presence of numerous reactive histiocytes, which are the opposite in lymphoma.
To differentiate Kikuchi disease from SLE using histopathology, Kikuchi disease is characterized by the absence or low number of hematoxylin bodies, plasma cells and neutrophils.
What cannot be seen in any of the three phases are neutrophils and eosinophils, and this will also be helpful in excluding infectious etiologies.
Immunohistochemical studies may also be important in diagnosing Kikuchi disease. The most important result to look out for is a positive Ki-M1P monoclonal antibody, which is present in Kikuchi disease but absent in malignant lymphoma.
How would you Manage this Patient?
At this point, you should have a fairly accurate diagnosis of Kikuchi disease, and should have eliminated all other differentials. If you have reached this point, then you can be fairly certain Sakura will do well, because Kikuchi disease is generally a self-limiting disease, which usually resolves within 1-6 months. As her doctor, you can offer her a range of supportive and symptomatic treatment, as follows.
You could prescribe her some nonsteroidal anti-inflammatory drugs or NSAID’s. This is used to relieve her of the cervical lymph node tenderness as well as her fever. Some examples are diclofenac sodium, ibuprofen etc. Regular antipyretics may be used to alleviate her fever.
Corticosteroids have also been proved to improve symptoms and cause quicker resolution of the disease. Their anti-inflammatory properties modify the hosts immune response to the supposed trigger factors, and produce a favorable outcome. Prednisone is the recommended example, and it is increasingly used in generalized Kikuchi disease or severe extra nodal involvement. The following indications may be used to justify use of corticosteroids
- Any signs of neurological involvement, for example, aseptic meningitis or cerebellar ataxia
- Signs of a severe SLE like syndrome, where antinuclear antibody (ANA) titers may be positive.
- Evidence of hepatic involvement, for example with increased LDH, AST, ALT levels.
These conditions warrant quicker use of corticosteroids— however, more recent studies suggest using them earlier on in less severe diseases, as it has proven to reduce frustrating symptoms despite NSAID therapy and allow faster resolution of the disease, allowing quicker return to work. For corticosteroid use, infection has to be ruled out.
However, in steroid resistant and recurrent cases, hydroxychloroquine may be prescribed. This is an antimalarial drug which is used to treat rheumatoid arthritis and SLE. Care should be taken when prescribing this as there are many adverse effects like eye and ear disorders. Intravenous immunoglobulins have also been used in the past.
Some studies have shown that the removal of the lymph node by excision has diagnostic as well as therapeutic benefits, with many patients showing improvement once the affected lymph nodes have been removed.
Follow up and Advice on Discharge
As mentioned before, Kikuchi disease is a generally self-limiting disease carrying an excellent prognosis. Resolution can be expected within 1-6 months. However, about 3-4% of adults and 31-39% of children may experience relapses, hence it is important to follow up and monitor for symptoms. Relapses have been associated with a high peripheral absolute lymphocyte count despite leukopenia. It is also important to monitor for SLE, as it has been shown to follow resolution of Kikuchi disease in some patients, though this is not very frequent.
It is important as a doctor, to educate the patient regarding this disease. In our case with Sakura, she must be reassured that she has a benign self-limiting condition, which will go away on its own with symptomatic treatment. This is essential, as she might have been frightened by the initial differential of lymphoma or TB. You must also educate her on the possible correlations of autoimmune conditions, and the importance of monitoring herself for further symptoms due to the risk of relapse.
What is the take away message from this case?
True, Kikuchi disease is not a deadly disease by any means, and it is quite harmless. However, the confusion it may have with its sinister differential diagnoses like lymphoma, TB and SLE, place it as an interesting and complex disease to establish. It is frequently misdiagnosed, and adverse treatment may be started which is of no benefit to the patient. Hence, knowing about the existence of this disease is important to the medical world, for all of us as professionals, and for the welfare of our patients.
References
https://emedicine.medscape.com/article/210752-overview#a1
https://www.ncbi.nlm.nih.gov/books/NBK430830/
https://rarediseases.info.nih.gov/diseases/6834/kikuchi-disease
https://rarediseases.org/kikuchis-disease/