Acute Monocytic Leukemia Masquerading Behçet's Disease-Like Illness at Onset in an Elderly Female

A previously healthy 74-year-old Japanese female was hospitalized with fever and high C-reactive protein. She developed palatal herpangina-like aphthous ulcers, localized intestinal wall thickening, terminal ileum ulcers, and an erythematous acneiform rash; thus Behçet's disease-like illness was suspected. Significant peripheral blood acute monocytosis developed during her hospitalization and acute monocytic leukemia (FAB M5b) with normal karyotype was diagnosed. By immunostaining, the infiltrating cells in the skin and the terminal ileum were identified as monocytic leukemic cells. This case exhibited a unique initial presentation of Behçet's disease-like illness associated with acute monocytic leukemia.


Introduction
Autoimmune diseases like Behçet's disease (BD) develop in as many as 10% of patients with myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) [1]. In particular, a link between BD or BD-like illness and chronic myelomonocytic leukemia (CMML) with a trisomy 8 chromosome abnormality has been well recognized [2][3][4]. However, the association of BD or BD-like illness and acute myeloid leukemia has rarely been reported [5]. In patients with CMML showing cutaneous lesions as a sign of BD or BD-like illness, skin tissues were shown to contain abnormal monocytes, that is, leukemia cutis [6][7][8]. We report here an elderly Japanese female who initially presented with BDlike illness including cutaneous lesions and thereafter was diagnosed as having acute monocytic leukemia (AMoL; FAB M5b). In this case, we identified leukemic cells in the tissues of skin and ileum.

Case Report
A previously healthy 74-year-old Japanese female was hospitalized with unknown fever and high C-reactive protein (CRP) values in December 2015. On admission, she was 155 cm in height and 59.2 kg in weight and had temperature of 37.6 ∘ C, blood pressure of 118/64 mmHg, pulse rate of 71/min, respiration rate of 18/min, and SpO 2 of 94% at room temperature. Physical examination revealed no specific findings. After admission, she developed herpangina-like aphthous ulcers at the palate, when significant monocytosis (absolute monocyte counts >5,000/ L) was first noted; however, monocytosis fluctuated ( Figure 1). Thereafter, a CT scan of the abdomen showed localized thickening of the intestinal wall (Figure 2(a)) and colonofiberscopy (CF) revealed the presence of multiple ovoid punched-out ulcers at the terminal ileum and aphthous lesions at the ascending colon ( Figure 2(b)). In addition, the patient also developed multiple erythematous rashes on her right thigh (Figure 3(a)). Given the diagnostic criteria of BD [9], the rash was not typical erythema nodosum but was thought rather to be acneiform eruption. Ophthalmological studies showed no evidence of BD signs. Taken together, BD was suspected in this patient from fulfilling 2 major and 1 minor clinical features required in the diagnosis of BD [9]. Thereafter, from the second week of admission, the patient again developed Blood results at the 5th week of admission, when AMoL was diagnosed, were as follows: white blood cells (33,200/ L) containing 15% blasts, 21% promonocytes, 19% mature monocytes, 1% myelocytes, 10% neutrophils, and 33% lymphocytes (Figure 4 90%), whose markers were CD4+ (59.2%) and CD8+ (27.4%), respectively. By contrast, the hypercellular BM consisted of 33.2% blasts, 15.0% promonocytes, 33.6% mature monocytes, 6.8% granulocytes, 1.4% lymphocytes, 2.0% plasma cells, and 8.0% erythroblasts with an M/E ratio of 0.85 (Figure 4 (Figures 2(c) and 2(d)). Also the histopathology of skin rash showed that the infiltrating cells were positive for lysozyme, CD13, CD14, and CD33 (Figures 3(b) and  3(c)). These findings confirmed that the lesions primarily thought due to BD-like illness were in fact AMoL-related. In addition, HLA-typing, performed to ascertain whether the patient had BD-related HLA types, detected the presence of A2/A24 and B52/B55 but not the BD-related HLA-B51 or B5 alleles [11,12]. As shown in Figure 1, the patient was initially treated with adalimumab for BD-like illness, following the successful report for a case of intestinal BD with trisomy 8 MDS by Kimura et al. [13]; however, after AMoL was confirmed, she was transferred to another hospital for intensive chemotherapy as a very high-risk patient.

Discussion
This case is not a classic autoimmune case of BD, nor is AMoL that developed during the treatment for BD. AMoL masquerading BD-like illness acutely developed. We had no evidence that this case progressed from CMML, because blood count records for the past 5 years prior to admission showed no increase of monocytes (which remained <10%) in the PB. Clinical features of BD, aphthous stomatitis, skin lesions, and ulcers in the terminal ileum were present, but genital ulcers, vascular, or ocular involvements were absent; thus, it was considered to be an incomplete BD or BD-like illness. The HLA-B51 allele was also absent. To date, the association of BD or BD-like illness with MDS has been well characterized, particularly in those patients with CMML [2][3][4][14][15][16], but rarely characterized in patients with acute myeloid leukemia [5]. The precise causes developing BD or BD-like illness in cases of MDS/CMML are unknown [17].
In immunostaining studies in a classic autoimmune case of BD, Yamana et al. [18] showed that the lymphocytes infiltrating the terminal ileum were high CD4 (Leu 3a) + cells and low CD8 (Leu 2a) + cells. On the other hand, Tada et al. [14] previously reviewed the clinical characteristics of MDSassociated BD or BD-like illness in Japan but did not mention the characteristics of infiltrating cells in the tissues. In CMML cases, leukemic cells were reported to infiltrate cutaneous tissues as leukemia cutis [6][7][8]. We confirmed that both the skin rash and ileal tissues were infiltrated with monocytic leukemic cells in the case presented here. It remains unknown however how these findings explain the development of BD or BD-like illness in a case of AMoL. In a classic autoimmune case of BD cytokine-producing dysfunctional T cells play a major role [19]. In our case, infiltrating monocytic leukemic cells or T cells responding to monocytic leukemic cells or both might have played a similar role by producing various cytokines. As another interesting issue, a literature survey indicates a correlation of BD or BD-like illness and MDS/CMML with the presence of chromosomal trisomy 8 [2-4, 15, 16]. The present case, in contrast, had no trisomy 8.
In summary, although rare, caution must be exercised if BD or BD-like illness is associated with any hematological diseases, such as MDS/CMML, or rarely AMoL. We presented here the unique clinical course of an elderly patient whose disease initiated with the clinical features mimicking BD and was followed by the diagnosis of AMoL (FAB M5b) with normal karyotype.