Pina-Oviedo Sergio, Medeiros L Jeffrey, Li Shaoying, Khoury Joseph D, Patel Keyur P, Alayed Khaled, Cason R Craig, Bowman Christopher J, Yin C Cameron
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2017 May;30(5):734-744. doi: 10.1038/modpathol.2016.235. Epub 2017 Jan 13.
Langerhans cell histiocytosis is characterized by a localized or systemic proliferation of Langerhans cells. BRAF mutations have been reported in 40-70% of cases and MAP2K1 mutations have been found in BRAF-negative cases, supporting that Langerhans cell histiocytosis is a true neoplasm, at least in mutated cases. In a small subset of patients, Langerhans cell histiocytosis is detected incidentally in a biopsy involved by lymphoma. These lesions are usually minute and rarely have been assessed for mutations. We assessed for BRAF and MAP2K1 mutations in seven cases of Langerhans cell histiocytosis detected incidentally in biopsies involved by lymphoma. We performed immunohistochemical analysis for phosphorylated (p)-ERK. There were four men and three women (median age, 54 years; range, 28-84). The biopsies included lymph nodes (n=6) and chest wall (n=1). The lymphomas included five classical Hodgkin lymphoma, one mantle cell lymphoma, and one angioimmunoblastic T-cell lymphoma. All cases were negative for BRAF V600E and MAP2K1 mutations. Nevertheless, three of seven cases showed ERK activation as shown by expression of p-ERK. We performed mutation analysis using a panel of 134 commonly mutated genes (including BRAF and MAP2K1) by next-generation sequencing on three cases, including two cases positive for p-ERK by immunohistochemistry. No mutations were detected in any of the three cases assessed. Six patients received therapy appropriate for their lymphoma. With a median follow-up of 21 months (range, 6-89), no patients developed disseminated or recurrent Langerhans cell histiocytosis. We conclude that lymphoma-associated Langerhans cell histiocytosis is a clinically benign process that is not associated with BRAF V600E or MAP2K1 mutations and, as suggested by others, the designation Langerhans cell hyperplasia may be more appropriate. Nevertheless, the expression of p-ERK in three cases suggests that the RAS-RAF-MAP2K-ERK pathway is activated, perhaps by non-mutational mechanisms induced by the presence of lymphoma or lymphoma-microenvironment interactions.
朗格汉斯细胞组织细胞增多症的特征是朗格汉斯细胞的局部或全身增殖。据报道，40%-70%的病例存在BRAF突变，在BRAF阴性的病例中发现了MAP2K1突变，这支持了朗格汉斯细胞组织细胞增多症是一种真正的肿瘤，至少在突变病例中是这样。在一小部分患者中，朗格汉斯细胞组织细胞增多症在淋巴瘤累及的活检中偶然被发现。这些病变通常很小，很少对其进行突变评估。我们对在淋巴瘤累及的活检中偶然发现的7例朗格汉斯细胞组织细胞增多症病例进行了BRAF和MAP2K1突变评估。我们对磷酸化（p）-ERK进行了免疫组化分析。患者中有4名男性和3名女性（中位年龄54岁；范围28-84岁）。活检标本包括淋巴结（n=6）和胸壁（n=1）。淋巴瘤包括5例经典型霍奇金淋巴瘤、1例套细胞淋巴瘤和1例血管免疫母细胞性T细胞淋巴瘤。所有病例的BRAF V600E和MAP2K1突变均为阴性。然而，7例病例中有3例显示出p-ERK表达所表明的ERK激活。我们对3例病例进行了二代测序，使用一组134个常见突变基因（包括BRAF和MAP2K1）进行突变分析，其中2例免疫组化显示p-ERK阳性。在评估的3例病例中均未检测到突变。6例患者接受了适合其淋巴瘤的治疗。中位随访21个月（范围6-89个月），没有患者发生播散性或复发性朗格汉斯细胞组织细胞增多症。我们得出结论，淋巴瘤相关的朗格汉斯细胞组织细胞增多症是一个临床良性过程，与BRAF V600E或MAP2K1突变无关，并且如其他人所建议的，朗格汉斯细胞增生这一名称可能更合适。然而，3例病例中p-ERK的表达表明RAS-RAF-MAP2K-ERK途径被激活，可能是由淋巴瘤的存在或淋巴瘤与微环境的相互作用诱导的非突变机制所导致。
