Loss of 5-Hydroxymethylcytosine Is an Epigenetic Hallmark of Melanoma

Ollier disease and Maffucci syndrome are characterized by multiple central cartilaginous tumors that are accompanied by soft tissue hemangiomas in Maffucci syndrome. We show that in 37 of 40 individuals with these syndromes, at least one tumor has a mutation in isocitrate dehydrogenase 1 (IDH1) or in IDH2, 65% of which result in a R132C substitution in the protein. In 18 of 19 individuals with more than one tumor analyzed, all tumors from a given individual shared the same IDH1 mutation affecting Arg132. In 2 of 12 subjects, a low level of mutated DNA was identified in non-neoplastic tissue. The levels of the metabolite 2HG were measured in a series of central cartilaginous and vascular tumors, including samples from syndromic and nonsyndromic subjects, and these levels correlated strongly with the presence of IDH1 mutations. The findings are compatible with a model in which IDH1 or IDH2 mutations represent early post-zygotic occurrences in individuals with these syndromes.

Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2

Objective  To quantify the accuracy and reproducibility of pathologists’ diagnoses of melanocytic skin lesions. Design  Observer accuracy and reproducibility study. Setting  10 US states. Participants  Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart. Main outcome measures  Pathologists’ interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, ≥pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses. Results  In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted. Conclusion  Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists’ visual assessments.

https://www.bmj.com/content/bmj/357/bmj.j2813.full.pdf

Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study

Many cancers have long been thought to primarily metabolise glucose for energy production - a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilise other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumour. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumour environment. Mutations in the tumour suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumour biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

/pdf/metabolic-reprogramming-in-glioma-31ajtr1t31.pdf

Metabolic Reprogramming in Glioma

Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia.

Isocitrate dehydrogenases (IDHs) catalyse oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). IDH1 functions in the cytosol and peroxisomes, whereas IDH2 and IDH3 are both localized in the mitochondria. Heterozygous somatic mutations in IDH1 occur at codon 132 in 70% of grade II–III gliomas and secondary glioblastomas (GBMs), and in 5% of primary GBMs. Mutations in IDH2 at codon 172 are present in grade II–III gliomas at a low frequency. IDH1 and IDH2 mutations cause both loss of normal enzyme function and gain-of-function, causing reduction of α-KG to D-2-hydroxyglutarate (D-2HG) which accumulates. Excess hydroxyglutarate (2HG) can also be caused by germline mutations in D- and L-2-hydroxyglutarate dehydrogenases (D2HGDH and L2HGDH). If loss of IDH function is critical for tumourigenesis, we might expect some tumours to acquire somatic IDH3 mutations. Alternatively, if 2HG accumulation is critical, some tumours might acquire somatic D2HGDH or L2HGDH mutations. We therefore screened 47 glioblastoma samples looking for changes in these genes. Although IDH1 R132H was identified in 12% of samples, no mutations were identified in any of the other genes. This suggests that mutations in IDH3, D2HGDH and L2HGDH do not occur at an appreciable frequency in GBM. One explanation is simply that mono-allelic IDH1 and IDH2 mutations occur more frequently by chance than the bi-allelic mutations expected at IDH3, D2HGDH and L2HGDH. Alternatively, both loss of IDH function and 2HG accumulation might be required for tumourigenesis, and only IDH1 and IDH2 mutations have these dual effects.

/pdf/screen-for-idh1-idh2-idh3-d2hgdh-and-l2hgdh-mutations-in-1zxwdwah9n.pdf

Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH Mutations in Glioblastoma

Dear Editor, Agaimy and Wunsch recently reported potentially misleading thyroid transcription factor 1 (TTF-1) immunoreactivity in a primary ovarian malignant mullerian mixed tumour [1]. This is one of several recent papers highlighting the danger of relying on TTF-1 expression in isolation as a marker of either lung or thyroid origin for a malignant tumour. Comperat et al. reported that 5% of primary colorectal adenocarcinomas expressed TTF-1 when assessed with Novocastra’s SPT24 clone [2]. Penman et al. also found that the SPT24 but not the 8G7G1 TTF-1 clone showed nuclear positivity in some colorectal adenocarcinomas [3]. We would like to highlight the observation that immunocytochemical TTF-1 positivity may be found in glioblastoma multiforme, which to our knowledge has not previously been reported. Usually, the distinction between glioblastoma multiforme and metastatic carcinoma is relatively easy to make on morphological grounds; however, there are some cases in which the tumour is poorly differentiated, and for such cases, immunocytochemistry may be of value in making this distinction. Following our observation in routine diagnostic practice of two cases of glioblastoma which showed positivity with antibodies to the SPT24 clone of TTF-1 (Fig. 1), a further 26 cases of glioblastoma multiforme and one case of gliosarcoma were assessed. In all cases, there were morphological, immunocytochemical, radiological and clinical features supporting the diagnosis of glioblastoma, and none had any evidence of metastatic disease or of any preexisting lower grade cerebral neoplasm. Immunocytochemical staining for the SPT24 (Novocastra) and 8G7G3/1 (Dako) TTF-1 clones, MNF116, CK7, CK20 and glial fibrillary acidic protein (GFAP) was performed in all cases. Staining for the TTF-1 clone SPT24 (Novocastra) was performed with 2 min of pressure cooking pretreatment in 2 l of 10 mM citrate buffer at pH 6.0. The primary antibody was diluted at 1:100 and incubated for one hour at room temperature. Standard ABC method was performed using Vector’s RTU Universal Elite ABC kit PKY200. The staining was developed for 10 min in diaminobenzidine. The technique for TTF-1 clone 8G7G3/1 (Dako) immunocytochemistry was identical, other than that the primary antibody was diluted at 1:50. To calculate percentages of positive cells, at least 500 presumed neoplastic nuclei per case were counted from the areas in which staining appeared most abundant. In total, fourteen glioblastomas (50%) showed some degree of nuclear positivity when stained with the SPT24 TTF-1 clone. This staining was patchy and variable between cases (ranging from 0.1 to 62.2% of nuclei). Nuclear positivity was seen in under 2% of cells in seven cases, between 2 and 10% of cells in three cases, and over 30% of cells in the other four cases. Positive neoplastic nuclei were not detected in the other fourteen cases of glioblastoma or in the gliosarcoma. All cases were negative when stained with the 8G7G3/1 TTF-1 clone. Staining for GFAP was positive in the cytoplasm of at least a proportion of the neoplastic cells in all cases. MNF-116 and cytokeratin 20 staining was negative in all cases. Cytokeratin 7 staining was negative in all cases of glioblastoma, but showed focal positivity in the spindle cell element of the gliosarcoma. Virchows Arch (2007) 451:109–111 DOI 10.1007/s00428-007-0432-5

TTF-1 staining in glioblastoma multiforme.

A 63-year-old man was admitted at the emergency department in an acute confusional state, and a computerized tomography scan (CT) revealed hydrocephalus. Despite the rapid introduction of a ventriculo-peritoneal shunt, the patient died soon thereafter. At the post-mortem examination, a large solid mass was found to be firmly attached to a nerve root at the L1-L2 level. Microscopically, the tumor showed the classical features of a malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation. In addition, there were randomly distributed lobules of well-differentiated adipose tissue with unequivocal atypical nuclei. The diagnosis of MPNST with rhabdomyoblastic and lipoblastic differentiation was made. We are not aware of previously reported lipoblastic differentiation in MPNST. Herein, we present details of the case.

Liposarcomatous differentiation in malignant peripheral nerve sheath tumor: a case report.

The authors report a very rare case of a vestibular schwannoma with an infiltrate of monoclonal plasma cells. A 45-year-old woman underwent routine excision of a presumed vestibular schwannoma. Histological analysis revealed the presence of a distinct lambda light chain restricted plasma cell population within the schwannoma. The light chain restriction and polymerase chain reaction-demonstrated monoclonality of the plasma cell population suggested the co-occurrence of a plasma cell neoplasm within a schwannoma. A search for systemic disease of plasma cell origin was unremarkable. A search of the literature suggests that this is the first report of such an occurrence.

Schwannoma with monoclonal plasma cell infiltration

Two cases in which a neurological disorder was identified pathologically to be due to a granulomatous infiltration were found after diagnosis to have an associated testicular seminoma with pathologically proven lymphatic metastasis. We present the clinical and imaging features, and pathological appearances of the lymphatic tissue and the brain. We summarise the literature to date and discuss the pathogenesis of the disorder and its treatment.

Granulomatous CNS inflammation associated with seminoma.

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