Kikuchi disease with skin lesions mimicking lupus erythematosus

Abstract

Background

Kikuchi disease (Kikuchi-Fujimoto disease, histiocytic necrotizing lymphadenitis) is a systemic illness of unkown etiology. It is characterized by cervical lymphadenopathy and fever. The skin is the most frequently affected extranodal organ. Cuta­neous Kikuchi-Fujimoto disease can mimic both clinically and histolo­gically skin lesions in lupus erythema­tosus, a disorder with which it seems to be closely related. A close follow up is required as systemic lupus erythema­tosus develop­ment has been reported.

Main observation

We report a case of a 23-year-old woman, who was admitted to our depart­ment with high fever, skin lesions and arthralgia. Scaly and erythematous plaques were noted on both cheeks and earlobes. In pads of feet and hands and periungual area, multiple purple papules with a perilesional erythematous halo were evident. A thoraco­abdominal computed tomography scan revealed lateral cervical, mediastinal, paratracheal, subcarinal and submandi­bular lympha­denopathy. Excisional node biopsy was consisten with Kikuchi disease with skin involvement.

Conclusion

It has to be kept in mind that Kikuchi disease is a differential diag­nosis in case of fever, lymphade­nopathy and lupus-like skin lesions. Skin lesions in this disease and may resemble clinically and histologically to those of subacute lupus erythema­tosus or systemic erythema­tosus lupus.

Introduction

Kikuchi-Fujimoto disease (KFD) know also as Kikuch disease or histiocytic necrotizing lymphadenitis is an entity of unkown etiology. It is characterized by cervical lympha­denopathy and fever. The skin is the most frequently affected extranodal organ. Cutaneous Kikuchi-Fujimoto disease can mimick both clinically and histolo­gically skin lesions in lupus erythematosus. A close follow up is required as systemic lupus erythema­tosus (SLE) develop­ment has been reported.[1]

Case Report

A 23-year-old woman with no relevant past medical history was admitted to our department of Dermatology with symptoms of high fever, skin lesions and arthralgia. Despite 2 weeks of previous broad-spectrum antibiotic therapy, the patient had had no clinical response.

The patient was in a relatively fair clinical condition. Physical exami­nation revealed palpable cervical lympha­denopathy. Scaly and erythe­matous plaques were noted on both cheeks and earlobes [Fig. 1A]. In pads of feet and hands and periun­gual area, multiple purple papules with a peri­lesional erythema­tous halo were evident [Fig. 1B]. Semi mucosa lip involve­ment with mild muco­sitis and small aphthous ulcers were also present. There were no signs of arthritis.

Figure 1.

(a) Scaly and erythe­matous plaques on both cheeks and nose. (b) Numerous purple papules with an erythematous halo are present in toes' pads.

Laboratory studies showed: haemo­globin (Hb) 9.7 g/dL; lactate dehydro­genase (LDH) 742 U/L, C reactive protein (CRP)108.2 mg/L: erythrocyte sedimen­tation rate (ESR) 57; total Immuno­globulin E 1925 UI/mL; antinuclear antibodies (ANA) titer 1/320 with speckled pattern and peripheral antineutro­phil cyto­plasmic antibodies (p-ANCA) 39 U/mL, and positive Coombs test (++/++++). Viral and bacterial serology tested nega­tive except for Epstein Barr Virus (EBV) Ac VCA IgG +, Ig M+, Ac EBNA +. Further labo­ratory findings were not relevant.

Two skin biopsies, performed from a periungual lesion and a facial papule, showed interface dermatitis with basal vacuolar dege­neration, colloid bodies and isolated necrotic keratinocytes [Fig. 2]. Papillary dermis showed edema and a linfohistiocytic perivascular and peria­dnexal infiltrate, with accumu­lations of histiocytes and karyorrhexis. Indirect immuno­flourescence was negative. No images of vasculitis were seen.

Figure 2.

Skin biopsy. (a) Interface dermatitis. Vacuolar layer degeneration and colloid bodies. (b) Lym­pho­histio­cytic aggregates with kariorrhexis.

On the echocardiography a slight pericardial effusion was detected. A thoraco­abdominal computed tomography scan revealed lateral cervical, mediastinal, para­tracheal, subcarinal and submandi­bular lympha­denopathy up to 1.7 cm of diameter.

Despite the fact that clinical and labo­ratory findings suggested a diagnosis of systemic lupus erythe­matosus, the extensive lymph node involve­ment forced us to rule out a lymphoma and tuberculosis, even though the skin histo­logy was not consistent.

Excisional lymph node biopsy confirmed the histolo­gical diagnosis. Para­cortical patchy necro­tic areas with abundant cellular debris and profuse peripheral hystio­citic cells were seen [Fig. 3]. AFB staining was negative.

Figure 3.

Lymph node biopsy. (a) Paracortical necrotic foci. (b) Necrosis and kariorrhexis.

A diagnosis of Kikuchi-Fujimoto Disease with skin involvement was made. Treat­ment was initiated with oral prednisone at a dose of 30 mg/day and hydrochlo­roquine at a dose of 200 mg/day. A clinical and analytical improve­ment was seen within the following weeks although arthralgia persisted for 6 months. The patient did not develop more skin lesions and the ANA titer lowered and remained low for 6 months.

Discussion

KFD or necrotizing lympha­denitis is a rare disease of unknown cause and pathoge­nesis, usually characterized by cervical lympha­denopathy and fever. Initially described in young women in Asia, there are now cases reported in all races. Some reports raised the hypo­thesis that previous infection is probably responsible for the massive CD4 T cells apopto­sis mediated by CD8 that occurs.[1] EBV RNA has been detected in the lymph nodes of some patients. This finding favors the patho­genic role of certain types of viruses, especially EBV, which could also be a fact in our patient.

Even though high fever and cervical lymphade­nopathy are the most common clinical mani­festations, neck and mediastinal nodal areas can also be affected. In addition, involvement of other organs is not un­common so clinical findings include auto­immune hepatitis, aseptic meningitis, neuritis, panuveitis and pancy­topenia. Atypical lympho­cytes without outliers are observed in 25% of patients. ANA test is positive in 7% of the cases.

Skin involvement occurs in 40% of cases of KFD, being the most frequently affected extra­nodal organ. A non-specific rash is usually found but other skin mani­festations such as acral leuco­cytoclastic vasculitis, malar erythema, oral aphthous ulcers, diffuse alopecia, pruritus, photo­sensitivity, pustules and lupus-like papules and plaques can also be seen. Lupus-like lesions of KFD are more similar to the skin lesions of subacute lupus erythema­tosus than to those of systemic lupus erythematosus. Small obser­vational studies have described a more intense skin involve­ment accordingly to more severe cases,[2] as well as more heterogeneous skin lesions correlated with an increased apoptotic activity.[3]

Specific KFD's skin histo­logical features have not been fully described, but the most common patterns are: dermal lympho­histiocytic infiltrate, epider­mal changes with occasional necrotic keratino­cytes, karyorrhexis, vacuolar layer dege­neration and dermal papillae edema.[4] These patterns are also frequent findings in SLE except for the last one. Dermal infiltrate is similar to that found in the lymph node with CD68+ histiocytes and plasma­cytoid monocytes.

Diagnosis is based on the exci­sional lymph node biopsy. The histo­logical features correspond to three evolving phases: early or proliferative, necro­tizing and xantho­matous phase. The most characte­ristic finding is the appearance of multiple foci of patchy para­cortical necrosis with a peripheral CD68+ cell and CD123+ plasma­cytoid dendritic cell infiltrate. In early stages, large lympho­cytes with immuno­blast morpho­logy may be increased which gives a picture resembling high-grade lymphoma. Plasma cells are scarce and neutro­phils and eosino­phils are characte­ristically absent. SLE lympha­denitis is considered as the most challenging differential diag­nosis but it can be distinguished from KFD by the presence of abundant plasma cells, a more diffuse involvement, vasculitis and typical un­common aggre­gates of nuclear debris or so-called hemato­xylin bodies.[5]

The most common labo­ratory findings are leukopenia and elevated values of ESR, C-reactive protein (CRP) and LDH.[6]

KFD is a self-limited condition with a 20% recurrence rate. However, systemic steroids may improve its evolution. A well designed prospective study found that predictive values of recurrence are fever, fatigue, extranodal involvement and long sympto­matic duration.[7] Some cases of fatal evolution have been reported.

KFD has been related to Cobalamin deficiency, Hemophagocytic Lymphohistiocytosis, Drug-induced hyper­sensivity syndrome, and several auto­immune diseases. A progression to SLE is a well-known fact, although its asso­ciation with exclusively cuta­neous lupus is rare.

Current knowledge of KFD is scarce and based on small case series so doubt remains on whether the disease should be considered as an independent entity of SLE.[8] Both conditions share common features as skin involvement, fever and lymphadenitis. Additio­nally, the histologic appearance of lymph nodes in patients with Kikuchi disease is similar to that of lymph nodes in patients with SLE lymphadenitis. Moreover, lympha­denitis is present in 50% of SLE cases and some authors recommend its inclusion in the SLE criteria.

Based on this data, KFD could be a "forme frustre" or an early stage of SLE. However, some other authors suggest that KFD is only an in­adequate apoptotic response to a previous infection. Based on retrospective obser­vational studies, basal layer vacuolar dege­neration in skin samples and elevated ANA have been proposed as markers of trans­formation into SLE.[9] A close follow-up with periodically ANA deter­mination is mandatory in these patients. Our opinion is that KFD and SLE may share a common patho­genic pathway and could be closely related.

Conclusion

In conclusion, we present a new case of KFD with skin involvement resembling clinical and histological skin lesions of Lupus Erythematosus. Our patient's high ANA titer makes us believe that she could develop SLE in the future. KFD is a major differential diag­nosis in case of fever, lymphadenopathy and lupus-like skin lesions especially when the patient is an Asian woman. Lymphoma and tuber­culosis should be considered as alternative diagnoses. Skin lesions are not uncommon in KFD and may resemble clinically and histologically to those of Subacute Lupus Erythematosus or Systemic Erythe­matosus Lupus. Diagnosis is based on excisional lymph node biopsy, showing multiple foci of patchy para­cortical necrosis. A close follow up of these patients is necessary, especially when a high ANA titer is present, in order to discard a progression to SLE.