Successful Management of Refractory Kimura Disease with CVP Chemotherapy: A Case Report

Background

Kimura disease is a rare chronic inflammatory disorder that primarily presents as a painless mass in the subcutaneous tissue of the head and neck region, often accompanied by lymphadenopathy. It may also involve the orbit, eyelid, lacrimal gland, and extraocular muscles [1]. The condition is characterized by an increase in peripheral blood eosinophilia and elevated level of immunoglobulin E. The diagnosis is established through pathological examination, which reveals the infiltration of lymphocytes and eosinophils among inflammatory cells, the formation of eosinophilic abscesses, proliferation of capillary and post-capillary venules, and increased fibrosis [2]. While the precise etiology remains unknown, pathological and laboratory findings suggest that allergic reactions and autoimmune responses may play a role in development of the disease. Therapeutic options to consider initially include surgical excision, corticosteroids, and radiation therapy. Additional treatments that have been reported in the literature include intravenous immunoglobulin (IVIG), tacrolimus, leflunomide, and biologic agents, including rituximab, dupilumab, and mepolizumab [3–5]. Although it shows some levels of recurrence following surgical treatment and corticosteroid therapy, malignant transformation of Kimura disease has rarely been reported [6].

Beyazit et al [7] reported a case in which a 35-year-old patient, who was initially diagnosed with Kimura disease with her pre-auricular lesion, was later suspected of developing malignant transformation into T cell lymphoma during follow-up observation, and subsequently received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Additionally, in Korea, there have been reported cases of NK/T cell lymphoma occurring during follow-up observation for Kimura disease [8].

The CHOP chemotherapy regimen is utilized for treatment of non-Hodgkin lymphoma and consists of cyclophosphamide, doxorubicin, vincristine, and prednisone. Each treatment cycle lasts for 3 weeks, with a total of 6–8 cycles typically administered. In patients with underlying cardiovascular disease, the cardiotoxicity of doxorubicin must be considered, and a CVP (cyclophosphamide, vincristine, prednisone) combination may be employed instead. Cyclophosphamide, an alkylating agent, damages cancer cell DNA, while vincristine inhibits cell replication by binding to the protein tubulin [9,10].

Here, we report a case in which CVP chemotherapy effectively controlled orbital Kimura disease that was unresponsive to conventional conservative treatments such as surgical intervention, corticosteroid, immunosuppressive treatment, and radiation therapy.

Case Report

A 64-year-old female patient presented with swelling and a palpable mass in her left upper eyelid, experiencing mild pain and ptosis in her left eye. She had a history of a diagnosis of Kimura disease in her right eye 3 years prior (Figure 1). After undergoing oral prednisolone treatment 20 mg for 2 weeks at that time, her symptoms improved, and there had been no recurrence until now. Upon physical examination, the mass in her left upper eyelid was firm and showed no tenderness. She has no other skin lesions or lymphadenopathy, and she exhibited none of the ‘B symptoms’ such as fevers, night sweats, or weight loss. Results of ophthalmic examinations, including visual acuity, intraocular pressure, and eye movement, were normal. A computed tomography (CT) scan of the orbit revealed a well-defined, peripherally enhancing mass, and magnetic resonance imaging (MRI) demonstrated a mass with peripheral enhancement on T1-weighted imaging, exhibiting mild diffusion restriction. The 5×15 mm mass was located in the preseptal area of her left upper eyelid and extended to the lacrimal gland and the size of the mass (Figure 2A, 2B). Blood tests showed an elevated eosinophil count of 11.4% (normal range up to ∼6.0%), IgE levels were 356 IU/ml, a positive FANA with a speckled pattern, and normal ranges of ESR (10 mm/h, normal range ∼15.0), CRP (0.01 mg/dL, normal range ∼0.5), WBC (412.0/uL), ANCA (negative), and RF (negative). A tissue biopsy revealed lymphoid infiltrates with scattered eosinophils, enabling a diagnosis of Kimura disease.

The patient was administered oral prednisolone (Yuhan Corporation, Seoul, Korea) 50 mg for 4 weeks, then reduced by 10 mg every 2 weeks. While initial improvement was noted, the symptoms continually recurred, and there was no visible decrease in the size of the lesion after treatment. The oral corticosteroid dosage was maintained at 10 mg, and an additional 36 Gy of modulated radiation therapy was administered. Three months after radiotherapy, the lesion measured 41×27 mm. Cyclosporine (Chong Kun Dang Pharm Corporation, Seoul, Korea) was added at a dosage of 250 mg twice daily, but there was no alleviation of symptoms. Subsequently, symptoms worsened, with severe eyelid swelling, decreased vision, and positive relative afferent pupillary defect, suggesting compressive optic neuropathy (Figure 3A). High-dose methylprednisolone 1 g (Reyon Pharm Co., Seoul, Korea) was administered intravenously for 3 days, and lateral orbitotomy was performed to reduce the mass and conduct an additional biopsy. Pathological examination revealed micro-abscess, stromal necrosis, and chronic lymphocytic inflammation, with no signs of malignancy.

Despite repeated treatments, the patient’s symptoms remained uncontrolled. Subsequent blood tests and an additional orbital MRI indicated an eosinophil percentage of 8.1% (normal: up to ∼6.0%), elevated immunoglobulin E at 128 IUml, a mass enlargement to 44×40 mm, and a reduced apparent diffusion coefficient (ADC) value to 0.67 (Figure 2C–2E). To investigate possibilities of malignancy, an additional ultra-sound-guided core needle biopsy was performed, revealing lymphoplasmacytic infiltrates with eosinophils in collagenous stromal tissue; however, no pathological indications of malignancy were confirmed (Figure 4).

Lastly, the patient received 6 rounds of CVP (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, prednisolone 100 mg) chemotherapy because the lesion was unresponsive to various treatments, and suspected malignancy in accordance with finding of MRI. After chemotherapy, an orbital MRI showed, dramatic reduction in the extent and size of the tumor, and the swelling of the left upper eyelid improved (Figure 3B). An orbital MRI conducted 6 months after CVP chemotherapy showed complete resolution of the previous lesions, and over 1 year of follow-up after the last dose of chemotherapy, the patient remained stable without recurrence of symptoms (Figure 5A, 5B).

Discussion

Kimura disease is recognized as a benign reactive condition, but its exact causes and pathogenesis are unknown. Observations of increased peripheral eosinophils, mast cells, and elevated IL-5 and IgE levels suggest the disease may involve an unusual T cell stimulation, akin to a hypersensitivity reaction [11]. Kimura disease is a chronic condition that typically has a slow, fluctuating progression, with periods of activity and remission. While surgery is the primary treatment method, regional or systemic corticosteroid therapy, cytotoxic treatment, and radiation have also been utilized [12,13]. It is frequently observed that the disease tends to recur following surgical intervention or upon cessation of steroid therapy [11].

The recurrence rate following surgical resection was 30.5%, while the rates following medication-only approaches, such as corticosteroids, cyclosporine, mycophenolate mofetil, target therapy, and radiation therapy (with doses ranging from 20 to 45Gy), were 45% and 60%, respectively. However, when surgical treatment was combined with adjuvant therapies, the recurrence rate was the lowest, at 26.94%. A meta-analysis suggested that the likelihood of recurrence after surgery is high when the maximum diameter of the tumor exceeds 3 cm, the duration of the disease exceeds 5 years, the peripheral blood eosinophil count exceeds 20%, or the serum immunoglobulin E exceeds 10 000 IU/ml. Therefore, adjuvant therapy may be necessary under these circumstances [14]. In this patient’s case, the mass measured 5×15 mm at the initial visit but a subsequent post-recurrence measurement showed a rapid increase to 44×40 mm. The eosinophil count was 11.4%.

While there have been a few reports of malignant transformation of Kimura disease, there is still no conclusive evidence of malignancy arising directly from the disease itself. Instead, concerns remain that each case may have been an initial mis-diagnosis or involved systemic malignancy [7,8]. In the present case, the disease remained unresponsive to conventional treatments, including surgical resection, corticosteroids, cyclosporine immunosuppression, and 36Gy of radiotherapy. Even though multiple biopsy examinations did not disclose any malignancy signs, the disease’s rapid progression and clinical manifestations, like optic nerve compression, suggested a possible malignancy. This suspicion was further supported by a low ADC value of 0.67 observed on MRI, which could indicate increased cellular density and high proliferative activity within the tumor and may signify the potential for malignancy in Kimura disease [15]. In conclusion, the administration of CVP chemotherapy effectively controlled the patient’s symptoms, with no recurrence or aggravation of the disease noted for approximately 1 year after the treatment. The alkylating action of cyclophosphamide, which damages DNA, and the cell replication inhibition caused by vincristine’s binding to protein tubulin, may have suppressed the high cell proliferation activity in this patient.

Beyazit et al [7] documented a case where a patient diagnosed with Kimura disease and under observation showed suspected malignant transformation to lymphoma, which was effectively managed through CHOP chemotherapy. A noteworthy difference between the present report and Beyazit et al’s report [7] lies in the initial diagnostic confirmation of Kimura disease; their case lacked such confirmation. In the present case, no signs of malignancy were found in several pathological examinations. The use of steroids or immunosuppressants before biopsy can interfere with the diagnosis of lymphoma [16], suggesting that, in cases like this one, continuous use of immunosuppressants, including corticosteroids, can hinder the confirmation of malignancy in pathological examinations. These insights suggest that clinicians should consider chemotherapy options such as CVP or CHOP in treating Kimura disease that is resistant to conventional treatment and exhibits high cell proliferation on MRI findings, even in the absence of pathological evidence of malignancy.

Conclusions

In conclusion, for individuals with Kimura disease who exhibit no response to conventional treatments, demonstrate rapid and atypical progression, and present with low ADC values on MR imaging suggestive of potential malignancy, the consideration of CHOP or CVP chemotherapy may be appropriate. This therapeutic approach remains plausible even in the absence of a clear malignancy diagnosis from pathological assessments. This case underscores the need for additional research into the potential malignancy of Kimura disease and the efficacy of CVP chemotherapy in managing uncontrolled manifestations of this disease.