Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis

The histological differential diagnosis between melanotic schwannoma, primary leptomeningeal melanocytic lesions and cellular blue nevus can be challenging. Correct diagnosis of melanotic schwannoma is important to select patients who need clinical evaluation for possible association with Carney complex. Recently, we described the presence of activating codon 209 mutations in the GNAQ gene in primary leptomeningeal melanocytic lesions. Identical codon 209 mutations have been described in blue nevi. The aims of the present study were to (1) perform a histological review of a series of lesions (initially) diagnosed as melanotic schwannoma and analyze them for GNAQ mutations, and (2) test the diagnostic value of GNAQ mutational analysis in the differential diagnosis with leptomeningeal melanocytic lesions. We retrieved 25 cases that were initially diagnosed as melanotic schwannoma. All cases were reviewed using established criteria and analyzed for GNAQ codon 209 mutations. After review, nine cases were classified as melanotic schwannoma. GNAQ mutations were absent in these nine cases. The remaining cases were reclassified as conventional schwannoma (n = 9), melanocytoma (n = 4), blue nevus (n = 1) and lesions that could not be classified with certainty as melanotic schwannoma or melanocytoma (n = 2). GNAQ codon 209 mutations were present in 3/4 melanocytomas and the blue nevus. Including results from our previous study in leptomeningeal melanocytic lesions, GNAQ mutations were highly specific (100%) for leptomeningeal melanocytic lesions compared to melanotic schwannoma (sensitivity 43%). We conclude that a detailed analysis of morphology combined with GNAQ mutational analysis can aid in the differential diagnosis of melanotic schwannoma with leptomeningeal melanocytic lesions.     

GNA11 and N‐RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system

M. Gessi, J. Hammes, L. Lauriola, E. Dörner, J. Kirfel, G. Kristiansen, A. zur Muehlen, D. Denkhaus, A. Waha and T. Pietsch (2013) Neuropathology and Applied Neurobiology 39, 417–425 GNA11 and N‐RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system Aim: Primary melanocytic tumours are uncommon neoplasms of the central nervous system. Although similarities with uveal melanomas have been hypothesized, data on their molecular features are limited. Methods: In this study, we investigated the mutational status of BRAF^V600E, KIT, GNAQ, GNA11, N‐RAS and H‐RAS in a series of 19 primary melanocytic tumours of the central nervous system (CNS). Results: We identified six cases harbouring mutations in the hotspot codon 209 of the GNAQ gene and two cases with mutations in the hotspot codon 209 of the GNA11 gene. Two mutations in codon 61 of N‐RAS were also found. In the single strand conformation polymorphism (SSCP) analysis, no shifts corresponding to BRAF^V600E mutations or suggesting activating mutations in the KIT gene were observed. Conclusions: In primary melanocytic tumours of the CNS, GNA11 and N‐RAS mutations represent a mechanism of MAPK pathway activation alternative to the common GNAQ mutations. On the other hand, BRAF^V600E mutations and activating KIT mutations seem to be absent or very rare in these tumours.     

Primary atypical melanocytoma arising from the cavernous sinus in a child

Introduction

Primary melanocytic lesions of the central nervous system originate from leptomeningeal melanocytes, with a spectrum ranging from well-differentiated benign meningeal melanocytomas to malignant melanomas. Atypical melanocytomas are borderline tumors, which have clinical and pathological characteristics between benign melanocytomas and malignant melanomas. Melanocytomas are rare in children and infrequently arise from the cavernous sinus. Approximately five patients with such an origin site have been reported.

Materials and methods

We report a 15-year-old girl with an atypical melanocytoma arising from the cavernous sinus. She underwent partial resection of the tumor and postoperative gamma knife surgery (GKS). She is stable 39 months after surgery.

Conclusion

We discuss the first pediatric case with an intracranial atypical melanocytoma arising from the cavernous sinus.

     

Primary cerebellopontine angle melanoma: a case report and review

Primary melanomas at the cerebellopontine (CP) angle are extremely rare and considered a diagnostic dilemma. With only 16 prior cases reported so far, there is not enough material in world literature. We report a 29-year-old male who presented with vertigo, headache and features of lower cranial nerve involvement with MRI revealing a melanotic lesion at CP angle. The patient underwent right suboccipital craniectomy and only subtotal excision of the tumor was possible. Histopathologically it turned out to be malignant melanoma. Since a thorough search for any possible primary was futile, it was considered a primary melanoma. Patient was given adjuvant radiotherapy. Ten months later, he presented with weakness and multiple spinal metastases and two months later he succumbed to his disease. We did a comprehensive review of literature about various melanocytic tumors at the CP angle. Pathologically, melanocytic tumors range from benign melanocytomas to malignant melanoma with variable prognosis. The clinical presentation depends upon whether the lesions are diffuse or discrete. Surgery is the primary modality of treatment and the amount of tumor excised is related to the prognosis. We conclude the discussion with a novel classification for melanotic tumors of CNS and the current diagnostic pathway for a melanotic lesion at the CP angle.     

WHO 2016 classification: changes and advancements in the diagnosis of miscellaneous primary CNS tumours

This short review highlights significant changes and recent findings incorporated to varying extent in the WHO 2016 definition of a variety of tumours, including peripheral nerve sheath tumours, meningiomas, mesenchymal nonmeningothelial tumours, melanocytic tumours, lymphomas and histiocytic tumours, germ cell tumours and non‐neuroendocrine pituitary tumours. Most notable classification changes include: adding ‘hybrid nerve sheath tumours’ to the spectrum of benign nerve sheath tumours; an updated definition of atypical meningioma (WHO grade II), including cases with brain invasion; recognizing dural solitary fibrous tumour (SFT) and haemangiopericytoma (HPC) as a single tumour entity characterized by NAB2 and STAT6 gene fusions for which the term SFT/HPC was chosen; recognizing that pituitary granular cell tumour, spindle cell oncocytoma, and pituicytoma all share nuclear expression of TTF‐1, possibly representing a spectrum of a single nosological entity derived from posterior pituitary glial cells. The most significant diagnostic markers which have emerged include: inactivation of NF1, CDKN2A, and PRC2 components, SUZ12 and EED in MPNST, leading to neurofibromin and H3K27me3 expression loss; GNAQ and GNA11 mutations in CNS primary melanocytic tumours; BRAFV600E mutation in histiocytic tumours (Langerhans cell histiocytosis and Erdheim‐Chester disease) and papillary craniopharyngioma, which provides both a diagnostic marker in the appropriate pathological setting and a therapeutic target. The WHO 2016 Classification has balanced cutting‐edge knowledge on the molecular characteristics of the miscellaneous CNS tumours reviewed here with a practical approach for their daily diagnostic work‐up. Much more progress can be expected in the classification of these neoplasms in the near future.     

Mutation analysis of the Ras pathway genes<Emphasis Type="Italic"> NRAS</Emphasis>,<Emphasis Type="Italic"> HRAS</Emphasis>,<Emphasis Type="Italic"> KRAS</Emphasis> and<Emphasis Type="Italic"> BRAF</Emphasis> in glioblastomas

Aberrant activation of Ras signaling is a common finding in human glioblastomas. To determine the contribution of Ras gene mutations to this aberration, we screened 94 glioblastomas for mutations in the three Ras family genes NRAS, KRAS and HRAS. All tumors were additionally analyzed for mutations in BRAF, which encodes a Ras-regulated serine/threonine kinase with oncogenic properties. Mutation analysis of the entire coding regions of NRAS and KRAS, as well as the known mutation hot-spot sites in HRAS, identified somatic point mutations in two glioblastomas, both affecting codon 12 of NRAS (c.35G>A, p.G12D). Three additional tumors carried BRAF mutations altering the known hot-spot codon 599 (c.1796T>A, p.V599E). None of these five glioblastomas showed amplification of the EGFR or PDGFRA genes, while three of the tumors, including two with NRAS and one with BRAF mutation, demonstrated PTEN missense mutations or loss of PTEN mRNA expression. Taken together, our data suggest activating mutations in NRAS or BRAF as a molecular alteration that contributes to aberrant Ras signaling in a small fraction of glioblastomas.     

Primary melanocytic tumors of the central nervous system: a neuroradiological and clinicopathological study of five cases and brief review of literature

Primary melanocytic tumors of the central nervous system (CNS) are uncommon lesions. These lesions arise from the melanocytes located within leptomeninges and include diffuse melanocytosis and meningeal melanomatosis (seen in neurocutaneous melanosis), melanocytoma, and malignant melanoma. To study, the clinical course, neuroradiological features, morphology and immunohistochemistry of primary melanocytic tumor of CNS. Demographic, clinical and surgico-pathologic findings of five patients with melanocytic tumors seen between 1996 and 2003 were studied. In this study, five cases of primary melanocytic tumors have been reported: four cases of malignant melanoma and one case of melanocytoma. Three of the 5 cases were intracranial and 2 were spinal. The mean age in the present study was 26 years. Presenting features varied according to the location. Primary melanocytic tumor of CNS are rare. Whenever possible, complete surgical excision is the best treatment.     

The diagnostic dilemma of primary central nervous system melanoma

Melanomas are malignant neoplasms of melanocytes developing predominantly in the skin, but occasionally arising from eyes, mucous membranes, and the central nervous system (CNS). The CNS can be affected by a spectrum of melanocytic lesions ranging from diffuse neurocutaneous melanosis, to a focal and benign neoplasm (melanocytoma), and to an overtly malignant tumor (melanoma). Primary melanocytic lesions involving the CNS are typically concentrated in the perimedullary and high cervical region. Primary CNS melanoma cannot be reliably distinguished from metastatic melanoma on neuroimaging and histopathological characteristics alone: its diagnosis is established only after exclusion of secondary metastatic disease from a cutaneous, mucosal or retinal primary. We present two patients with primary CNS melanoma and discuss relevant issues, available treatment options, and expected outcomes. Awareness of disease spectrum and clinico-biological differences may be used to guide therapeutic decision-making for a patient with a proven or suspected primary CNS melanoma.     

Primary melanocytic neoplasms of the central nervous system

Primary melanocytic neoplasms of the central nervous system (CNS) are rare lesions arising from melanocytes of the leptomeninges. They include diffuse leptomeningeal melanocytosis or melanomatosis, melanocytoma and primary malignant melanoma. We have reviewed the English literature regarding these lesions, which consists of case reports and a small number of larger case series. The presenting features, radiological, surgical and histological findings are reviewed, as are current management options and prognosis. We also present illustrative case reports of diffuse leptomeningeal melanocytosis and primary melanoma of the CNS.     

中枢神经系统原发性黑色素肿瘤的临床特征及病理特征分析

目的探讨中枢神经系统原发性黑色素肿瘤的临床表现、病理特征及手术效果。方法回顾性分析2003年3月至2017年2月手术治疗的3例中枢神经系统原发性黑色素性肿瘤的临床资料,1例位于颞叶,1例位于小脑,1例位于右侧桥小脑角区。结果 2例全切,1例次全切。术后随访1~3个月,3例一般情况良好。结论中枢神经系统原发性黑色素肿瘤确诊依赖病理检查,临床分型对判断预后有重要意义。     

Primary melanocytic lesions of the CNS: report of five cases

Primary melanocytic tumours of the central nervous system (CNS) form a rare entity which is histologically and clinically distinct from metastatic cutaneous or retinal malignant melanoma. They can be classified into diffuse melanocytosis (diffuse melanosis), malignant melanoma and benign melanocytoma with a small number of intermediate variants. In this paper, 5 cases treated neurosurgically in our department for spinal or cerebral primary CNS malignant melanoma are reported. Primary tumors and further metastases were ruled out. Radiological, histological and clinical features are discussed. Compared to metastatic disease, primary CNS malignant melanoma shows a more benign clinical course with long-term tumour control and a good quality of life. A review of the literature which mainly consists of individual case reports, confirms this assessment. Although therapeutic experience for primary melanocytic lesions of the CNS is based on a small number of published cases, prognosis seems highly dependent on complete tumour resection. Adjuvant radiation seems to be of additional therapeutic benefit. Except for meningeosis melanomatosa chemotherapy must be regarded as experimental. Unfortunately, a standardised therapy concept is still lacking.     

Pathology of intracranial neoplasms.

This article discusses the gross and microscopic pathology of intracranial neoplasms. Primary intracranial neoplasms include tumors of the brain parenchyma; meninges; and rest of mesenchymal, epithelial, and germ cell derivation. The concept of tumor malignancy for primary central nervous system (CNS) neoplasms is somewhat different from that for systemic tumors. Although the capacity to metastasize is a defining feature of systemic malignancies and metastasis to the brain is a relatively common occurrence, primary CNS neoplasms rarely metastasize outside the CNS.     

TP53, β-Catenin and c-myc/N-myc status in embryonal tumours with ependymoblastic rosettes

M. Gessi, A. zur Muehlen, L. Lauriola, M. P. Gardiman, F. Giangaspero and T. Pietsch (2011) Neuropathology and Applied Neurobiology 37, 406–413
TP53, β‐Catenin and c‐myc/N‐myc status in embryonal tumours with ependymoblastic rosettes Background: The primitive neuroectodermal tumours of central nervous system (CNS‐PNET) are a heterogeneous group of neoplasms, occurring in the CNS and composed of undifferentiated or poorly differentiated neuroepithelial cells which may display divergent differentiation along neuronal, astrocytic and ependymal lines. The WHO classification includes in this group of tumours also ependymoblastomas and medulloepitheliomas. Several groups have reported examples of CNS‐PNET with combined histological features of ependymoblastoma and neuroblastoma, defined as ‘embryonal tumour with abundant neuropil and true rosettes’. The presence of the amplification of chromosome region 19q13.42, common in both ependymoblastoma and embryonal tumour with abundant neuropil and true rosettes, suggests that they represent a histological spectrum of a single biological entity. Methods: We examined 24 cases of ependymoblastoma/embryonal tumour with abundant neuropil and true rosettes (EPBL/ETANTR) for the presence of mutations of TP53 and β‐Catenin and for amplification of c‐myc/N‐myc. Results: The single strand conformation polymorphism‐mutational screening did not identify any mutation in exons 5 to 8 of the TP53 gene. However, we found a point mutation affecting codon 34 (GGA→GTA) of β‐Catenin gene resulting in a Glycine → Valine substitution. No cases presented c‐myc/N‐myc amplification. Conclusions: EPBL/ETANTRs show molecular features different from other CNS‐PNET and medulloblastomas. The presence of alterations in the β‐Catenin/WNT pathway seems to be noteworthy due to the close relationship between this pathway and miR‐520g encoded in chromosome 19q13.42 region amplified in these tumours.     

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in the tumors of central nervous system (CNS)

Malignant neoplasms of the central nervous system (CNS) account for about 1.3 % of all tumors and 2.2 % of all cancer-related deaths. CNS tumors consist of heterogeneous group of neoplasms, including different variants of primary brain tumors and metastatic neoplasms. Advanced imaging techniques improved the neuroradiological diagnostic accuracy, although these methods are not specific enough for differentiation of CNS tumors, thus new approaches of patients’ diagnosis are critically needed. The best solution for the diagnosis of patients with CNS tumors could be easily available biomarkers, which could be useful for the management of CNS neoplasms. Biomarkers should facilitate the diagnosis, monitor of treatment response and assess the prognosis of patients’ survival. Currently, except for rare germ cell tumors, there is a lack of knowledge on biochemical markers for CNS neoplasms. Therefore, in this paper we summarized and referred a number of comprehensive reviews concerning the role of matrix metalloproteinases (MMPs) and their tissue inhibitors in tumor progression, including CNS neoplasms as well as described the general biochemistry of MMPs and their tissue inhibitors. Moreover, we presented the wide variety of previous findings, where authors suggested the significance of selected MMPs and their tissue inhibitors as potential biomarkers of human tumors, including CNS tumors. However, future investigations are needed to be performed before some of these enzymes could finally be used as biomarkers of specific types of CNS neoplasms.     

Microtubule-associated protein-2 immunoreactivity: a useful tool in the differential diagnosis of low-grade neuroepithelial tumors

Complex and variable morphological phenotypes pose a major challenge to the histopathological classification of neuroepithelial tumors. This applies in particular for low-grade gliomas and glio-neuronal tumors. Recently, we and others have identified microtubule-associated protein-2 (MAP2) as an immunohistochemical marker expressed in the majority of glial tumors. Characteristic cell morphologies can be recognized by MAP2 immunoreactivity in different glioma entities, i.e., process sparse oligodendroglial versus densely ramified astrocytic elements. Here, we describe MAP2-immunoreactivity patterns in a large series of various neuroepithelial tumors and related neoplasms (n=960). Immunohistochemical analysis led to the following conclusions: (1) specific pattern of MAP2-positive tumor cells can be identified in 95% of glial neoplasms; (2) ependymal tumors do not express MAP2 in their rosette-forming cell component; (3) tumors of the pineal gland as well as malignant embryonic tumors are also characterized by abundant MAP2 immunoreactivity; (4) virtually no MAP2 expression can be observed in the neoplastic glial component of glio-neuronal tumors, i.e. gangliogliomas; (5) malignant glial tumor variants (WHO grade III or IV) exhibit different and less specific MAP2 staining patterns compared to their benign counterparts (WHO grade I or II); (6) with the exception of melanomas and small cell lung cancers, MAP2 expression is very rare in metastatic and non-neuroepithelial tumors; (7) glial MAP2 expression was not detected in 56 non-neoplastic lesions. These data point towards MAP2 as valuable diagnostic tool for pattern recognition and differential diagnosis of low-grade neuroepithelial tumors.     

Frequency of seizures in patients with newly diagnosed brain tumors: a retrospective review

Brain tumors may lead to symptomatic epilepsy. A retrospective analysis was undertaken to evaluate the frequency of seizure as the presenting symptom leading to brain tumor diagnosis in adults. One hundred and forty-seven consecutive patients with newly diagnosed brain tumors were analyzed regarding the frequency of seizures as the initial presenting symptoms and those subsequently developing seizures. One hundred twelve patients had primary central nervous system tumors (CNS) and 35 had metastatic lesions. Statistical evaluation was carried out using the Chi-square test with p values of <0.05 considered to be statistically significant. Astrocytomas and meningiomas were the most common primary CNS tumors in this study. Of these, oligodendrogliomas and grade 2 astrocytomas were significantly more likely to present with seizures (p<0.001). Seizures were a frequent presenting symptom, occurring in over 38% of those with primary brain neoplasms and 20% of those with cerebral metastases. Primary location of tumor also correlated amongst primary CNS tumors and was associated with a trend in seizure risk: parietal (80%); temporal (74%); frontal (62%); and occipital (0%) (p<0.5). The findings highlight the importance of obtaining appropriate evaluation for underlying malignancy in adults with new-onset seizures as well as provide more information to the patient for prognosis and counseling.     

Intraventricular melanocytoma diagnosis confirmed by gene mutation profile

Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i.e. BRAF or NRAS) confirmed the diagnosis of an intraventricular melanocytoma. This case report is the second intraventricular melanocytoma published to date and demonstrates the value of applying novel genetic assays to make this diagnosis.     

Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology

Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to differentiate between oligodendrogliomas/oligoastrocytomas and other tumors with similar morphology. A total of 274 brain tumors presenting with focal or extensive clear cell morphology were investigated. High numbers of H09-positive cases were observed in adult grade II oligodendrogliomas (67 of 74, 91%), grade III oligodendrogliomas (65 of 69, 94%), grade II oligoastrocytomas (11 of 14, 79%) and grade III oligoastrocytomas (10 of 11, 91%). All cases of pediatric oligodendrogliomas (n = 7), neurocytomas (n = 41, 35 central, 4 extraventricular, 2 cerebellar liponeurocytomas), dysembryoplastic neuroepithelial tumors (n = 21), clear cell ependymomas (n = 8), clear cell meningiomas (n = 9) as well as 12 primary glioblastomas with oligodendroglial differentiation and 5 pilocytic astrocytomas with oligodendroglial-like differentiation were negative for H09 immunohistochemistry. Three oligodendrogliomas with neurocytic differentiation had evidence of IDH1/IDH2 mutations either by H09 immunohistochemistry or direct sequencing. We conclude that in tumors with an oligodendroglioma-like morphology, binding of H09 is highly specific for oligodendrogliomas or oligoastrocytomas and substantially helps in the discrimination from other clear cell tumors. Negative H09 immunohistochemistry of an adult oligodendroglioma or oligoastrocytoma should prompt the consideration of other clear cell neoplasms. Further, our observations firmly assign oligodendrogliomas with neurocytic differentiation to the group of oligodendrogliomas and demonstrate that H09 is especially helpful for the difficult discrimination of such lesions from extraventricular neurocytomas.     

Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing

Diffusely infiltrating cerebral gliomas frequently carry point mutations in codon 132 of the isocitrate dehydrogenase 1 (IDH1) gene or in codon 172 of the IDH2 gene, which are both clinically important as diagnostic and prognostic markers. Here, we report on a method that allows for the rapid detection of IDH1 and IDH2 mutations based on pyrosequencing. The method is applicable to routinely processed tissue specimens and provides quantitative mutation data within less than one working day. Due to its high sensitivity, the technique may also be used for the diagnostic assessment of IDH1 or IDH2 mutation in tissue samples with low tumor cell content, such as the infiltration zone of diffuse gliomas. Using pyrosequencing and/or conventional cycle sequencing of IDH1 and IDH2 in 262 gliomas, we confirm frequent mutations in diffuse astrocytic and oligodendroglial gliomas, corroborate a prognostic role for IDH1 mutation in primary glioblastomas and show that pleomorphic xanthoastrocytomas generally lack mutations in these genes.