Evaluation of Clinicopathologic Characteristics and the BRAF V600E Mutation in Erdheim-Chester Disease Among Chinese Adults

Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis with a broad, non-specific clinical spectrum. Here, we retrospectively evaluated the clinical and pathologic characteristics, presence of the BRAF V600E mutation, treatment options and outcomes of Chinese patients diagnosed with ECD at our center.

Methods Patients diagnosed with ECD between January 2010 and April 2015 at Peking Union Medical College Hospital were included for study. We evaluated baseline characteristics, reviewed histological material, and tested for the presence of the BRAF V600E mutation using immunohistochemistry and polymerase chain reaction (PCR).

Results Sixteen patients were diagnosed with ECD. Median age at diagnosis was 47 years (range, 22-61 years). Median disease duration (from the first symptom to diagnosis) was 22.5 months (range, 3-100 months). The main sites of involvement included bone (93.8%), cardiovascular region (43.8%), skin (31.3%), central nervous system (25.0%), and ¡°hairy kidney¡± (25%). Thirteen patients displayed characteristic histological features, including foamy histiocyte infiltration of polymorphic granuloma and fibrosis or xanthogranulomatosis, with CD68-positive and CD1-¦Á- negative immunostaining. Three patients (designated 3, 5 and 10) displayed CD68-positive and CD1¦Á- negative histiocyte infiltration, but not the above histological characteristics, and were thus initially misdiagnosed as Rosai-Dorfman disease. All three cases were BRAFV600E mutation-positive, leading to revision of diagnosis as ECD. Diagnosis of ECD in each case was additionally supported by typical radiographic findings. The BRAF V600E mutation was detected in 68.8% patients using PCR and 50.0% patients with immunohistochemistry. Ten patients (62.5%) received IFN-¦Á as first-line treatment, 3 patients showed improvement, 3 remained stable, 3 were too early for evaluation and 1 died. Three patients (5, 10 and 11) underwent transsphenoidal pituitary lesion surgery but were not subjected to systemic treatment, owing to the absence of symptoms and disease activity post-surgery and remained stable after a median of 16 months (range, 6-30 months) from diagnosis. Thirteen patients (81.3%) were still alive at median follow-up of 14.5 months.

Conclusion ECD remains a largely overlooked disease, and increased recognition by clinicians and pathologists is necessary for effective diagnosis and treatment. The presence of the BRAF V600E mutation may facilitate discrimination of ECD from other non-Langerhans cell histiocytoses.

Table 1. Characteristics and treatment of 16 patients with ECD

Patient	Sex/ age, years	Disease duration, mo	Main sites of involvement	BRAF IH	BRAF V600E	Therapy	Vital Status	OS£¬mo
1	M/33	5	B	N/A	-	IFN-6 MIU 3/wk	Alive	15
2	M/22	43	S, B	-	-	IFN-3 MIU 3/wk	Alive	11
3	M/25	18	B, LN, CNS	-	+	Pred	Dead	13
4	F/28	3	S, B	+	+	None	Alive	16
5	M/60	27	B, PIT	+	+	Surgery	Alive	15
6	F/61	5	B, H, LV, R£¬CNS, MS, S	N/A	+	IFN-6 MIU 3/wk	Dead	25
7	F/23	67	S, B, H, LV	-	-	IFN-3 MIU 3/wk	Alive	19
8	M/60	43	B, P, LV, R	N/A	+	IFN-6 MIU 3/wk	Alive	14
9	M/46	84	CNS, B	+	+	IFN-6 MIU 3/wk	Alive	22
10	F/51	7	PIT	+	+	Surgery	Alive	6
11	F/36	72	PIT, B	+	+	Surgery	Alive	30
12	M/55	100	B, S, CNS, PIT	-	+	IFN-6 MIU 3/wk	Alive	3
13	F/50	11	B, H	N/A	+	IFN-6 MIU 3/wk	Alive	5
14	F/46	8	B, LV, P	+	+	IFN-6 MIU 3/wk	Alive	1
15	M/52	30	B, LV, R, P£¬E	-	-	IFN-6 MIU 3/wk	Alive	1
16	M/47	4	B, LV, R, LN	-	-	None	Dead	36

Age is at diagnosis£»disease duration is from the first symptom to diagnosis

IH, immunohisochemistry; B, long bones; LN, lymph nodes; LV, large vessels; H, heart; S, skin; CNS, central nervous system; MS, maxillary sinus; PIT, pituitary gland; R, retroperitoneal; P, pericardial effusion; E, Exophthalmos; MIU, million international units; N/A, not available