Clinicopathological features and BRAF^V600E mutations in patients with isolated hypothalamic-pituitary Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is characterized by the idiopathic proliferation of specialized bone marrow-derived Langerhans cells and mature eosinophils. LCH can affect any organ or system and may be systemic or localized [1, 2]. Patients with isolated hypothalamic-pituitary (HP) LCH are very rare, although patients with multisystemic LCH often show pituitary gland involvement [3‐7]. Among the endocrine regions, LCH is frequently found in the HP region, resulting in diabetes insipidus (DI), the most common endocrine anomaly [8‐12]. Anterior pituitary involvement also occurs as a result of the disease process. However, anterior pituitary dysfunction is not invariably associated with abnormal HP region imaging, and it is almost always encountered in patients with multisystemic disease who show DI and HP pathology on magnetic resonance imaging (MRI) [6, 8]. The anterior pituitary endocrine function changes in isolated LCH limited to the HP region have been poorly studied.

Recently, LCH patients were shown to have a high frequency of BRAF^V600E mutations and to respond to RAF inhibitors, suggesting that LCH is more likely a neoplastic than a reactive disorder. The BRAF^V600E mutations are present in approximately 25–60 % of LCH cases [13‐20], but this mutation has not been reported in isolated HPLCH in previous publications.

Several studies on LCH patients, which examined relatively small numbers of patients, have provided information on the evolution of pituitary dysfunction as well as the morphological changes in the HP region [3‐7]. However, no large studies have examined patients with isolated HPLCH and assessed the pituitary function without interference from other organs. In the current study, we retrospectively studied seven patients with isolated HPLCH in our hospital from 2007 to 2015 and analysed their clinical and pathological features, endocrine function changes, BRAF^V600E mutations, and treatment outcomes.

Langerhans cell histiocytosis (LCH) is a rare heterogeneous histiocytic disorder, and the dominant sites of involvement are bone and adjacent soft tissue, liver, spleen and bone marrow [1, 2, 15]. The central nervous system (CNS) may also be involved [2, 21]. In patients with LCH in the HP region, most cases are extended from osseous foci in multifocal or disseminated LCH, but unifocal or multifocal infiltrates can occur primarily within or even restricted to the HP region and other sites, such as the infundibulum, optic chiasm, and choroid plexus [2‐7, 22, 23]. However, isolated HPLCH without the involvement of other organs is a rare condition, and there are few reports on the various characteristics of this disease state, including the evaluation of pituitary function, especially anterior pituitary function, the BRAF^V600E mutation status, and other clinicopathological features. Here, we reviewed seven cases of isolated LCH limited to the HP region and investigated the clinicopathological characteristics, endocrine function changes, BRAF^V600E mutations and treatment of the lesions.

The aetiology of the histiocytic lesions is largely unknown [1, 2]. Although the underlying aetiology of the condition has long been enigmatic, recent studies have suggested that LCH is due to clonal neoplastic proliferation of myeloid-derived precursor cells, with a high frequency of somatic oncogenic BRAF^V600E mutations in 25–60 % of LCH patients [13‐20]. In CNS, BRAF alterations are found in variable frequencies across a wide spectrum of diverse neoplasms, such as various glial and glioneuronal tumours, craniopharyngiomas, LCH and brain metastases [16]. No association between the BRAF^V600E mutation and survival has been found in LCH, but several case reports described an impressive response to a BRAF inhibitor in patients with BRAF V600E-mutated LCH [19]. As an independent condition, the data on the BRAF ^V600E mutation in isolated HPLCH is unclear, and one reason for this may be the low number of cases. In this report, we examined seven cases of isolated HPLCH, and we had sufficient quantities of tissue for mutation detection in six cases. The results of our study showed that BRAF^V600E was mutated in 50 % of patients with HPLCH, suggesting that the mutation rate in isolated HPLCH is consistent with the reported rates in LCH involving other sites. Because the follow-up time for some patients was short in our study, the relationship of BRAF^V600E mutation and survival was not analysed. Smoking is an important factor in primary LCH of the lung [17], but all seven patients had no history of smoking in our study, suggesting that smoking is not related to HPLCH.

Clinically, LCH can occur at any age but typically occurs in the paediatric population [1, 6, 10]. The most common neurological signs of LCH are CDI with or without associated signs of hypothalamic dysfunction, increased intracranial pressure, cranial nerve palsies, and seizures [2]. Isolated CDI may be an early diagnostic signature in patients with an abnormal lesion in the HP region and no past medical history, and the association of polyuria-polydipsia suggests that a complete endocrine evaluation and a meticulous MRI examination of the HP region should be performed [2, 4, 6‐10]. Patients with unifocal disease are usually older children or adults [1]. In our cohort, four patients were children aged 9–15 years, and three patients were adults. Our study had slightly more children with isolated HPLCH than adults. There was no specific gender preference in our study, which had slightly more females than males. The most common sign was CDI (polyuria and polydipsia, 100 %), and other symptoms included secondary amenorrhoea (1/7) and growth retardation (1/7).

While CDI is the most common HP symptom, anterior pituitary deficiencies are less common. Several studies have shown that most patients with HP lesions had one or more anterior pituitary deficiencies, and hormone deficiencies may be present at diagnosis or appear gradually during the course of disease [2‐8, 11]. Regular monitoring of these patients is recommended. Growth hormone deficiency is the most frequent disease-related anterior pituitary deficiency and is found in up to 50 % of patients, followed by gonadotrophin deficiency, but ACTH and TSH are relatively less common; moderately elevated PRL levels are infrequently found and are attributed to pituitary stalk involvement [8]. Established deficiencies almost never recover over time. In our cohort, more than a half of the patients with HPLCH had anterior pituitary deficiencies at diagnosis with a mean interval from the first symptoms to diagnosis of 42 months. Three patients were diagnosed with normal anterior pituitary functions, and the intervals from the first symptoms to diagnosis were less than 2 months for all of them. Our study suggested that the interval from the first symptoms to diagnosis may be related to the anterior pituitary function, and the lesions progressed with time. All patients had posterior pituitary deficiencies at diagnosis, and polyuria and polydipsia were the first symptom in all patients; thus, a MRI scan is necessary for patients presenting with polyuria and polydipsia.

MRI changes in patients with LCH of CNS include the following: 1) intracranial, extra-axial changes of the hypothalamic-pituitary region (50 %), meninges (29 %) or choroid plexus (6 %); 2) intracranial, intra-axial changes of white matter and gray matter (36 %); and 3) cerebral atrophy (8 %) [2]. There are several studies on the MRI changes in HPLCH, and pituitary stalk thickening can be observed in LCH in the HP regions [4, 6]. In our cohort, the MRI features of patients with HPLCH included the following characteristics: 1) a single lesion on the HP region and involvement of the pituitary stalk; 2) isointensity signals on both T1WI and T2WI in most cases; 3) homogeneous enhancement in most cases; 4) relatively clear borders in most cases. Although these are characteristic MRI findings, it is difficult to distinguish HPLCH from other diseases, such as germinoma or lymphocytic thyroiditis.

An accurate pathological diagnosis of LCH is necessary for further treatment and follow-up depending on the classic pathomorphological and immunohistochemical features. Recently, the use of neuroendoscopic biopsy for suprasellar masses has increased, and with this technique, it is possible to obtain an accurate pathological diagnosis [24], although sometimes the pathological diagnosis is difficult due to small specimens with prominent sampling artefacts and haemorrhage [25]. Distinguishing this condition from other diseases that can cause CDI, such as craniopharyngioma, germinoma, sarcoidosis, hypophysitis, and tuberculosis, is essential [2, 10, 26], and the pathological signature with both CD1a-positive, Langerin-positive, and S-100-positive infiltrating histiocytes and increased presentation of eosinophils has made the differential diagnosis relatively easy. In addition, differentiation from other non-Langerhans cell histiocytoses, such as Erdheim-Chester disease or Rosai-Dorfman disease, is also important. Although S-100 positive cells can be found in Erdheim-Chester disease (ECD) and Rosai-Dorfman disease, CD1a is always negative in the same histiocytes [1, 2]. Notably, the BRAF^V600E mutation was detected in more than 60 % of patients with ECD [27], but this mutation could not distinguish ECD from LCH because it was detected in approximately 25–60 % of the latter samples [13‐20]. In our cohort, the seven isolated HPLCH cases that we assessed had been confirmed by pathomorphological changes and immunohistochemical findings during neuroendoscopic transnasal transsphenoidal surgery, including six cases by biopsy and one by resection, and all cases were simultaneously positive for CD1a, Langerin and S-100. In addition, we evaluated the status of other organs in all patients, which is required to exclude the multisystemic lesions, and there was no evidence of other system involvement in all patients.

The overall 5-year survival rate of LCH patients is 88 %. Patients with unifocal LCH have an excellent prognosis and a high long-term survival rate (99 %) and may spontaneously recover or require minimal treatment [1, 28]. In our cohort, one patient died of liver disease, but we had no evidence of liver involvement with LCH; the other six patients were still alive, and further follow-up should be performed. No lesions were spontaneously recovered in our study. The treatments for LCH involving the CNS, such as conservative treatment, surgical intervention, chemotherapy and radiotherapy, were dependent on the lesion location, size, number and symptoms, and high-dose corticosteroid therapy was also used to control the inflammatory process. Additionally, CyberKnife radiosurgery was performed in some patients [2, 21, 28‐30]. However, the treatment of HPLCH patients is controversial because localized radiotherapy and chemotherapy were associated with tumour regression and stabilization but did not appear to prevent the evolution or deterioration of LCH-associated endocrine deficiency [3‐7, 30]. In our cohort, although remission was observed in the lesions of two patients after radiotherapy (30.5 Gy) and the lesion of another patient who received surgical resection after CyberKnife radiosurgery failure, the patients’ quality of life was irreversibly impaired because they had irreversible permanent sequelae, panpituitary hormone deficiency, and needed to receive goal-directed hormone replacement therapy and monitor hormone level changes permanently. The anterior pituitary function of another patient who received high-dose corticosteroid therapy only also progressed from GH and LH-FSH deficiency to panpituitary hormone deficiency. Our study suggested that the treatment of patients with HPLCH is a difficult problem, and the deterioration of the endocrine function appeared to be unrelated to lesion regression; thus, diagnosis and treatment as early as possible are essential. In addition, monitoring the whole body to assess multisystemic involvement is also very important. Moreover, for patients with BRAF^V600E mutations, new targeted therapies, such as vemurafenib, may be used because the results have been encouraging in select progressive patients with LCH [17, 31]. Recently, Nakagawa et al. [12] reported two relapsed females with LCH limited to the pituitary stalk and found that chemotherapy with cytarabine may be useful for preventing anterior pituitary hormone deficiency and neurodegenerative disease for new-onset CDI with LCH, but the further studies are needed to confirm these results.

Our study has some limitations as it is based on a small group of selected patients due to the low incidence of this condition. Notably, the follow-up time is short in our study because neuroendoscopic biopsy is a new technique in recent years, and it will be necessary to follow-up the patients over a longer period of time.

Our study indicated that some cases of isolated LCH involve only the hypothalamic-pituitary region, and all patients had CDI as the earliest symptom, with more than half having anterior pituitary deficiencies. The BRAF^V600E mutation is a common genetic change in HPLCH patients. The treatment of HPLCH patients is difficult, and the loss of endocrine function is irreversible in most cases. For patients with the BRAF^V600E mutation, new targeted therapy may be used when the lesion is progressing.