Valérie Rigau

BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy

PURPOSE Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined. PATIENTS AND METHODS BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. RESULTS Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). CONCLUSION In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

Lack of complete 1p19q deletion in a consecutive series of 12 WHO grade II gliomas involving the insula: a marker of worse prognosis?

Abstract1p19q codeletion in WHO grade II glioma (GIIG) is claimed to be a marker of better outcome and chemosensitivity. Through the molecular study of 12 insular GIIG, our goal was to investigate a possible anatomo-molecular relationship in insula, specific brain sub-region, known to be involved with high frequency in GIIG. Loss of heterozygosity on 1p and 19q chromosomes was assessed in all tumors. None complete deletion of the 1p and 19q arms chromosomes and partial deletions in 3 patients were retrieved in the 11 WHO grade II oligodendrogliomas and one oligo-astrocytoma analyzed. Discrepancy between our results and the high reported incidence of 1p19q codeletion in oligodendrogliomas could mean that insular GIIG has a specific molecular pattern. We hypothesize that prognosis of insular GIIG is worse than in other locations, with reduced chemosensitivity. Thanks to minimization of surgical risks, surgery might be a first intention therapeutic option proposed in the GIIG.

Bier anaemic spots, cyanosis with urticaria-like eruption (BASCULE) syndrome: a new entity?

DEAR EDITOR, Bier anaemic spots (BAS) are characterized by multiple asymptomatic anaemic white macules, which usually stand out against a cyanotic background and are mainly distributed on the extensor surface of the upper and lower extremities. Herein, we report four cases of a new dermatosis characterized by BAS associated with cyanosis and urticarialike eruption. In case 1, a 14-year-old girl with no relevant medical history was admitted for the evaluation of disseminated pruritic cutaneous lesions, which had appeared 2 years previously and were progressively worsening. The lesions developed after 1–2 min in a standing and immobile position, were associated with disabling pruritus and were relieved by sitting, walking around or raising the limbs. Cutaneous examination after 1–2 min in a standing position revealed multiple irregular white spots, which stood out from a marked cyanotic background. During the next few minutes, pruritic red– orange papules progressively appeared. These red–orange papules were located on the white macules, extending from their centre to cover most of their surface (Fig. 1a, b). The lesions faded completely within minutes of lying down (Fig. 1c). Histopathological examination of a biopsy specimen from a papule showed multiple dilated capillaries of the upper dermis with rare interstitial and scattered eosinophils and mast cells (Fig. 1d). Treatment with desloratadine (10 mg per day for 7 days) resulted in partial improvement of the pruritus, whereas the cutaneous lesions remained unchanged. In case 2, a 15-year-old girl with no relevant medical history was seen for the evaluation of pruritic cutaneous lesions of the lower limbs, which had appeared 10 months earlier. The lesions developed when the patient was in a standing and immobile position and were relieved by sitting or walking around. The patient also reported ankle oedema after more than 20 min of immobile standing. Clinical cutaneous findings after 1 min in a standing position were quite similar to those of the previous case. H1-antihistamines and tranexamic acid provided no relief. In case 3, a 19-year-old man with no relevant medical history was seen for asymptomatic white spots of the lower limbs, which had appeared 18 months earlier. Cutaneous

Successful treatment of recurrent extramammary Paget's disease of the penis and scrotum with imiquimod 5% cream

Figure 1 A. Extramammary paget’s disease of the scrotum and the base of the penil shaft. B. Biopsy of the scrotum displaying large epithelioid round cells with pale staining cytoplasms and hypertrophic nuclei (Hematoxylin & Eosin, 400). C. Scrotum and penis one month following completion of imiquimod 5% cream application. D. Biospy of the scrotum one month following completion of imiquimod 5% cream application: no evidence of Paget’s cells (Hematoxylin & Eosin, 200) Extramammary Paget’s disease (EMPD) is rare intra-epithelial adenocarcinoma involving primarily the epidermis. Cases affecting the penis and scrotum are rare [1], as involvement of male genitalia is found in less than 14% of the cases [2]. Surgery with a 2 to 3 cm margin followed by reconstruction remains the mainstay of treatment [3]. However, recurrence rate remains high and surgery has often significant consequences for the functional anatomy with irreparable tissue damage. Efficacy of imiquimod 5% cream has been assessed in different locations of female and male genitalia EMPD [2,4– 9]. We report here a successful treatment with imiquimod for relapsing peno-scrotal EMPD after multiple relapse after surgery.

PD1 and PDL1 expression in primary central nervous system diffuse large B‐cell lymphoma are frequent and expression of PD1 predicts poor survival

Primary central nervous system diffuse large B‐cell lymphoma (PCNS‐DLBCL) is a rare and aggressive type of diffuse large B‐cell lymphoma (DLBCL) whit poorly understood pathogenesis. Finding biomarkers associated with patient survival may be important for understanding its physiopathology and to develop new therapeutic approaches. We investigated 32 PCNS‐DLBCL from immunocompetent patients for BCL2, CMYC, LMO2, and P53 expression and for cytogenetic aberrations of BCL2, BCL6, and MYC genes, all known for their prognostic value in systemic DLBCL (s‐DLBCL). We analyzed PD1 and PDL1 protein expression in both tumor infiltrating lymphocytes (TILs) and tumor cells. Finally, we searched for correlation between biological data and clinical course. The PCNS‐DLBCL expressed BCL2, CMYC, LMO2, and P53 at similar frequency than s‐DLBCL but without significant prognostic on survival. None cases harbored aberrations involving BCL2 and MYC gene whereas BCL6 abnormalities were present in 20.7% of cases but without value on survival. Expression of PD1 in TILs and PDL1 in tumor cells was observed at higher rates than in s‐DLBCL (58% and 37%, respectively). The PD1 expression in TILs correlated with PDL1 expression in tumor cells (P = .001). Presence of PD1 positive TILs was associated with poorer overall survival (P = .011). Patients with PDL1 overexpression tended to better response to chemotherapy (P = .23).

Extensive thrombotic purpura revealing multiple myeloma associated - type I cryoglobulinemia.

A 69-year-old Caucasian male was hospitalized for recurrent attacks of ‘cutaneous vasculitis’ resistant to oral corticosteroids. On admission, he presented with extensive purpuric necrotic patches of the dorsum of the hands, the lumbar areas and the lower limbs (image). The lesions were sharply demarcated and mildly painful. The face and trunk were spared. The patient also described arthralgia of the knees and heels. Two 4-mm punch skin biopsies were performed in the centre and on the edge of a necrotic plaque. Microscopy showed noninflammatory hyaline thrombosis of the small blood vessels in the upper and deep dermis. There were no signs of cutaneous vasculitis or embolism (bottom right). Direct immunofluorescence (DIF) did not show any immunoglobulin deposits. Laboratory findings revealed an inflammatory syndrome with elevated C-reactive protein [145 mg/l, normal range (NR) <5 mg/l]. Hypogammaglobulinaemia was noted, with all immunoglobulins being below normal: immunoglobulin (Ig)G 3Æ02 g/l (NR 6Æ90–14Æ0 g/l), IgA 0Æ57 g/l (NR 0Æ7–4Æ1 g/l) and IgM <0Æ17 g/l (NR 0Æ34–2Æ40 g/l). A circulating type I IgG kappa cryoglobulin was detected, with reduced complement C4 but no rheumatoid factor activity. Tests for cryofibrinogenaemia, antiphospholipid antibodies and autoantibodies were negative. A bone marrow aspirate showed 63% of atypical plasmacytes. The final diagnosis was myeloma-related type I cryoglobulinaemia revealed by diffuse cutaneous small vessel thrombosis. Cutaneous manifestations of type I cryoglobulinaemia include inflammatory macules and papules, haemorrhagic crusts, ulcers, cutaneous infarction, scarring and livedo reticularis. The head and neck including the oral and nasal mucosa are the most common sites, but lesions can also occur on the extremities or trunk. Cutaneous infarction presents as irregular, sharply demarcated, purple to black necrotic patches with ‘geographic map’ or ‘puzzle piece’ distribution. Skin biopsy is mandatory to determine the diagnosis and must be performed on the most recent lesions. Noninflammatory hyaline thrombosis suggests type I cryoglobulinaemia, whereas vasculitis is uncommon. Eosinophilic amorphous materials maybe seen within vessels, suggesting cryoglobulin. DIF is often positive and in our case may have been falsely negative as it was performed on an ‘old’ lesion. Demonstration of type I monoclonal cryoglobulinaemia should prompt the search for an underlying lymphoproliferative disorder.

The scalp hair collar and tuft signs: A retrospective multicenter study of 78 patients with a systematic review of the literature

Background: Hair collar sign (HCS) and hair tuft of the scalp (HTS) are cutaneous signs of an underlying neuroectodermal defect, but most available data are based on case reports. Objective: We sought to define the clinical spectrum of HCS and HTS, clarify the risk for underlying neurovascular anomalies, and provide imaging recommendations. Methods: A 10‐year multicenter retrospective and prospective analysis of clinical, radiologic, and histopathologic features of HCS and HTS in pediatric patients was performed. Results: Of the 78 patients included in the study, 56 underwent cranial and brain imaging. Twenty‐three of the 56 patients (41%) had abnormal findings, including the following: (1) cranial/bone defect (30.4%), with direct communication with the central nervous system in 28.6%; (2) venous malformations (25%); or (3) central nervous system abnormalities (12.5%). Meningeal heterotopia in 34.6% (9/26) was the most common neuroectodermal association. Sinus pericranii, paraganglioma, and combined nevus were also identified. Limitations: The partial retrospective design and predominant recruitment from the dermatology department are limitations of this study. Conclusions: Infants with HCS or HTS are at high risk for underlying neurovascular anomalies. Magnetic resonance imaging scans should be performed in order to refer the infant to the appropriate specialist for management.

Romiplostim-induced erythromelalgia in a patient with idiopathic thrombocytopenic purpura

SIR, Thank you for the opportunity to respond to the letter of Apfelbacher and Hankins on our article ‘Validity and responsiveness of the Osnabrück Hand Eczema Severity Index (OHSI): a methodological study’. In their letter, the authors emphasize the importance of validation studies for instruments that assess the severity and change in hand dermatitis. We are pleased by the authors’ support and appreciate any suggestion that might improve our work or the work of any other research group facing the obstacles of a validation study. Besides the Manuscore, there are other instruments available that could be used as ‘gold standards’. All instruments mentioned in the letter were already mentioned in our study. Neither of the other two instruments is validated to such an extent that it presents itself as the choice sine qua non as ‘gold standard’. As we described in our paper, we used the Manuscore for practical reasons. The main focus of our validation study was responsiveness to change. Therefore the Hand Eczema Severity Index and the photographic guide had no advantage over the Manuscore – as none of the three instruments has so far been validated in a longitudinal study for responsiveness to change. To measure responsiveness to change we compared changes in the scores after treatment between the two measurement instruments by using effect sizes. We stated that the effect sizes preto post-treatment were not different between the Manuscore and the OHSI scoring and showed similar clinically meaningful improvements in the OHSI scores over 1 year. Because of space restrictions we had omitted the following Table (Table 1). Ninety per cent of the patients with improved results based on Manuscore scoring also exhibited improved results in the OHSI. Unchanged and worsened results were so scarce based on the Manuscore scoring that no meaningful conclusion for the comparison between the two instruments can be drawn. We conclude our paper with the sentence: ‘To affirm the validity of the OHSI a larger cohort is needed’. An additional conclusion – as recommended by the letter of Apfelbacher and Hankins – is: ‘As a gold standard other scores should be considered in further studies’.

EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity: EWSR1-PATZ1 gene fusion

We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1‐PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1‐PATZ1 fusion transcript. RT‐PCR followed by Sanger sequencing confirmed the EWSR1‐PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N‐terminal transcriptional activation domain of EWSR1 gene and the C‐terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB‐ZF (broad‐complex, tramtrack and bric‐à‐brac ‐zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1‐PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAFV600E negative ganglioglioma, the second a BRAFV600E negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAFV600E negative gangliogliomas were screened by FISH using EWSR1 break‐apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well‐defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1‐PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.

Towards an Intermediate Grade in Glioma Classification

Glial tumors are known to be difficult to classifify. Due to insights in genetic alterations of gliomas the 2016 WHO classification of tumors in CNS presents a new diagnostic approach introducing integrated histological and molecular diagnosis in the classification of diffuse gliomas. This approach will probably lead to better reproducibility between pathologists than histopathological criteria alone. However, the classification still defines histological grades of malignancy, and histologic grade is still an important factor in deciding treatment. For diffuse infiltrating gliomas the grades are GII (LGG), GIII and GIV (HGG). GII gliomas, despite their low grade, are infiltrative and will progress to higher grades of malignancy. The duration of transition from GII to GIII is highly variable. Identification of predictive markers of malignant progression could help identify patients who could benefit from early adjuvant treatments. We have studied the heterogeneity within GII gliomas, and find that some tumors harbor foci with histopathological and molecular features similar to higher grade. We suggest that these foci may represent initiation of malignant transformation. The term GII+ could be applied to these tumors indicating an intermediate grade, and the identification of these tumors can be valuable in order to optimize individual treatment.