Cutaneous Kikuchi Disease

Benign histiocytic necrotizing lymphadenitis or Kikuchi disease (KD) is a rare disease of unknown etiology first reported in 1972 in Japan by Kikuchi and later that year by Fujimoto and his colleagues.[1, 2] KD is most common in Asians and typically affects females younger than 40 years. It presents with persistent low-grade fever and enlargement of the cervical lymph nodes.[3, 4, 5, 6] The presence of lymphadenopathy with systemic symptoms often raises concern for lymphoma, prompting lymph node biopsy. Lymph node histopathology of KD is diagnostic, revealing characteristic necrosis, histiocytic infiltration, and karyorrhectic debris without neutrophils.[7] In up to one third of cases, KD may have skin findings.[3] This subset of disease is known as cutaneous KD. Numerous reports have cited an association between KD and systemic and cutaneous lupus erythematosus, with a diagnosis of lupus erythematosus either preceding or following the diagnosis of KD.[8, 9, 10, 11, 12] Fortunately, KD is usually self-limited, resolving on its own in 1-4 months. Systemic steroids and/or NSAIDs can be given to hasten resolution if symptoms are severe.[9, 13] Patients are expected to make a full recovery, although they should be monitored for the development of lupus erythematosus.

The pathogenesis of Kikuchi disease (KD) is unknown. Investigators have postulated that apoptosis plays an important part in the pathogenesis of KD, as apoptosis leading to necrosis is a prominent finding in both lymph nodes and skin affected by KD. Activated cytotoxic T cells, plasmacytoid monocytes, and CD68-positive histiocytes are commonly found on biopsy, suggesting that these cell types play a role in initiating and/or maintaining the inflammation that ultimately leads to apoptosis and necrosis. An autoimmune or viral trigger may be the inciting event that initiates the inflammatory cascade, although no antigen or viral trigger has been consistently identified.[14]

The etiology of Kikuchi disease (KD) is not yet known, but most authorities favor either an infectious or an autoimmune etiology. The association of KD with lupus erythematosus especially has prompted consideration of an autoimmune etiology for KD, but as yet, no pathogenic antigen has been identified. Reports have also described viral triggers for KD, including Epstein-Barr virus, parvovirus B19, and human herpesvirus 8, but no definitive causative pathogen has been identified and other studies failed to isolate viral material from lymph nodes of patients with KD.[7, 15, 16] It is possible that the etiology is related to an environmental trigger in a genetically susceptible individual that leads to the initiation of an autoimmune-mediated inflammatory process. Studies have demonstrated immunoglobulins and complement deposition at the dermoepidermal junction and in dermal blood vessel walls, which may support an autoimmune basis for KD.[17] Furthermore, studies have demonstrated an increased risk of disease in patients with certain HLA haplotypes, specifically HLA-DPA1 and HLA-DPB1. These alleles are more common in Asian patients, which helps explain the predominance of disease in Asia and supports the idea that there is a genetic susceptibility to this disease.[9]

Frequency

Kikuchi disease (KD) is more prevalent among Asians and is a relatively common disorder among Koreans.[18] It has been reported worldwide, but it is rare in European countries and the United States.[9] Cutaneous KD may arise in 16.6-40% of patients with KD,[19] with one study of 91 patients reporting cutaneous involvement in a third of cases.[3]

Race

This disease affects Asians more than other races, but it has been reported worldwide.[9]

Sex

Females are more commonly affected than males, with a female-to-male ratio of 4:1.[3, 20]

Age

KD can affect a wide range of ages from childhood to adulthood, with a mean patient age in the third decade. It is most common in patients younger than 40 years.[9, 21]

Kikuchi disease (KD) is a self-limited condition. Therefore, the prognosis overall is excellent. Most studies site recurrence rates of around 3-4%,[9, 14] although one study had a higher recurrence rate of 20%.[3]

Besides the pain associated with the condition, it has minimal mortality and morbidity. However, KD can evolve into lupus erythematosus, in which case morbidity and mortality are substantially increased. Patients who have cutaneous KD may have an increased risk of developing systemic lupus erythematosus and thus should be closely monitored.[3] One study by Dumas et al examined 91 patients with KD.[3] Of these patients, 12% had a known diagnosis of systemic lupus erythematosus at time of their KD diagnosis and another 13% of patients were diagnosed with systemic lupus erythematosus at the same time as KD or within the year following their KD diagnosis. This study found that cutaneous disease, arthralgias, weight loss, and a positive antinuclear antibody titer greater than 1/320 were significantly associated with an increased risk of developing systemic lupus erythematosus after a diagnosis of KD.

Patients should know that Kikuchi disease (KD) is a benign and self-limited condition. However, they should also be aware of the association of KD with systemic and/or cutaneous lupus erythematosus and that the risk may be increased if they have cutaneous KD.[3]

Kikuchi disease (KD) commonly presents with painful cervical lymphadenopathy accompanied by systemic symptoms such as fever, arthralgias, myalgias, anorexia, weight loss, night sweats, and chills. Hepatosplenomegaly and aseptic meningitis have also been reported.[3, 9] Cutaneous lesions, known as cutaneous KD, are relatively common and may occur in about one third of patients.[3] These cutaneous eruptions are varied and may include erythematous indurated papules or plaques, nodules, acneiform eruptions, or urticarial lesions. The eruption favors the upper body, especially the head and neck.[9, 14]

A prior history of autoimmune disease is often elicited in patients with KD. One study reported that 12% of patients with KD had a preceding diagnosis of systemic lupus erythematosus, which is the most commonly associated autoimmune disease.[3] Cutaneous lupus erythematosus, including discoid lupus and subacute cutaneous lupus, may also be associated with KD.[8, 9, 10, 11, 12, 22] Other associated autoimmune diseases include systemic sclerosis, antiphospholipid antibody syndrome, rheumatoid arthritis, Hashimoto thyroiditis, and Wegner granulomatosis.[3, 23] Therefore, it is important to take a thorough medical history in patients with possible KD to elicit any of these associated and possibly predisposing conditions.

Physical examination most commonly demonstrates cervical lymphadenopathy in Kikuchi disease (KD), although other lymph nodes may be involved, such as the axillary or supraclavicular nodes. Lymphadenopathy is usually painful.[9] Cutaneous KD occurs in about one third of patients (16-40%) and is often of a nonspecific nature.[3, 24] Most cutaneous lesions present as erythematous macules, papules, plaques, nodules, or ulcers on the upper part of the body, such as the trunk, the upper extremities, and the face.[9, 14, 25]

Several reports in the literature highlight the different physical examination findings associated with cutaneous KD. For example, Kim et al[26] reported a case of KD with a papulopustular eruption over the torso, arms, and legs. Imai et al[27] described a patient with lip edema. This patient had facial, neck, and arm desquamation and erosions, as well as transient indurated erythematous papules. Kaur et al[28] described a patient with Kikuchi disease with erythema multiforme–like lesions and a facial rash.

Other atypical presentations include oral ulcers, vesicles,[29] and eyelid edema.[30]

Kikuchi disease (KD) usually resolves on its own in a matter of months without sequelae. However, KD can evolve into lupus erythematosus (either systemic or cutaneous). Therefore, long-term follow up and counseling patients about this risk is prudent.

No laboratory abnormalities specific to cutaneous Kikuchi disease (KD) have been reported, but there are frequent reports of nonspecific lab abnormalities, including elevated erythrocyte sedimentation rates and C-reactive protein, leukopenia (especially granulocytopenia, which can occur in 20-58% of cases), thrombocytopenia, and atypical lymphocytosis reported in the peripheral blood.[3, 9, 31] Leukocytosis has been reported in 2-5% of cases. Elevated liver enzymes and lactate dehydrogenase may also occur.[3] In other cases, no laboratory abnormalities are identified.[9]

Interestingly, up to 45% of patients may have an elevated antinuclear antibody (>1/320). These patients appear to be at increased risk for developing lupus erythematosus or may have previously had a lupus erythematosus diagnosis.[3]

Cutaneous Kikuchi disease (KD) does not require any imaging studies. However, imaging studies, including computed tomography scans, may be performed to help diagnose the primary lymph node involvement of KD. Many different patterns of computed tomographic findings in KD have been reported. They include enlarged lymph nodes with a hypodense center and peripheral ring enhancement. Many small, clustered lymph nodes also may be a characteristic imaging feature of KD.[32]

Although not commonly done, flow cytometric studies performed on the affected lymph node, bone marrow aspirate, or peripheral blood reveal a relative expansion of mature activated T lymphocytes, predominantly expressing a CD8-positive phenotype.[33]

Skin biopsy is required for definitive diagnosis of cutaneous Kikuchi disease (KD), and lymph node biopsy is often performed to diagnose KD in general.

Skin biopsy specimens show a superficial and/or deep lymphohistiocytic infiltration with vacuolar interface dermatitis, necrotic keratinocytes, and prominent karyorrhexis in the absence of neutrophils. Mucin deposition has also been reported. These findings parallel the nodal histology of Kikuchi disease (KD), which typically shows patchy, well-circumscribed areas of necrosis with abundant karyorrhectic debris and large accumulations of histiocytes as well as lymphocytes. Neutrophils are absent. Importantly, lupus lymphadenitis is very difficult to distinguish from nodal KD, and in some cases it may be histologically and immunohistochemically indistinguishable.[9, 13, 34]

In 2010, Kim et al reported that in16 patients with cutaneous KD, 100% of skin biopsy specimens showed superficial lymphohistiocytic infiltration and karyorrhexis, 75% showed vacuolar interface dermatitis, and 68.8% showed necrotic keratinocytes.[34] Deposition of mucin was noted in 31.3%, and panniculitis was seen in 60%. One study by Pradela et al noted that the presence of interface dermatitis on skin biopsy of cutaneous KD was associated with an increased risk of progression to systemic lupus erythematosus.[13]

Of note, cutaneous KD shares many histologic features with cutaneous lupus erythematosus, such as interface dermatitis and dermal mucin deposition. However, a patchy, perivascular infiltrate with necrosis and karyorrhectic debris, as well as a lack of plasma cells, are features that support a diagnosis of KD over lupus erythematosus.[13, 34]

Immunohistochemistry findings demonstrate that the predominant infiltrating cells are CD3-positive T lymphocytes and CD68- and CD163-positive histiocytes. A slight predominance of CD8-positive lymphocytes was reported in approximately 81% of the patients in one study. CD20-positive B cells are rare.[9, 34]

See the image below.

Very high magnification micrograph of histiocytic necrotizing lymphadenitis, also known as Kikuchi disease. Hematoxylin and eosin stain. Courtesy of Nephron (own work), via Wikimedia Commons.

Once the diagnosis of Kikuchi disease (KD) is established, no specific medical care is indicated because this is a self-limited condition. NSAIDs or systemic steroids can be used if symptoms are severe as these may aid resolution.[35] Hydroxychloroquine is another option that has been effective in the treatment of KD.[36] It may be an especially good option for cutaneous KD or KD associated with lupus erythematosus.[3, 14] Hydroxychloroquine in combination with systemic steroids has also been used to successfully treat recurrent KD.[37, 38]

No surgical care is needed aside from performing a lymph node biopsy to make the diagnosis.

Consultation from a dermatologist, a pathologist, a surgeon, and an otolaryngologist can be helpful in establishing the diagnosis.

Long-term monitoring of patients with Kikuchi disease (KD) is required because KD carries a risk of progression to systemic and/or cutaneous lupus erythematosus. This risk ranges from 13-25% in the literature.[39] Therefore, patients should be warned of symptoms to watch for and should continue to see doctors regularly.

No specific medical therapy is indicated for Kikuchi disease (KD), but, as noted earlier, NSAIDs, systemic steroids, or hydroxychloroquine may be helpful if symptoms are severe or do not resolve on their own.