A novel low‐grade nasopharyngeal adenocarcinoma characterized by a GOLGB1‐BRAF fusion gene

Nasopharyngeal adenocarcinoma is a rare malignancy that is classified into conventional/surface‐ and salivary‐types. Herein we report the case of a 52‐year‐old male who presented with a right nasopharyngeal mass and right‐sided hearing loss. Diagnostic imaging revealed a circumscribed 1.7 cm mass centred in the right antero‐lateral aspect of the nasopharynx. A biopsy showed a gland‐forming neoplasm that was in continuity with the surface epithelium. The tumor exhibited a nested to micro‐papillary architecture, with mild cytologic atypia. Immunohistochemistry demonstrated diffuse staining for CK7, SOX10, and p16; the abluminal layer was highlighted by CK5 and p63, while the luminal cells expressed CD117. The tumor was not amenable to subclassification and was diagnosed as a low‐grade nasopharyngeal adenocarcinoma, not otherwise specified (NOS). Subsequent RNA sequencing was performed which identified a novel GOLGB1‐BRAF fusion product. Based on its unique morphology and molecular findings, this is presumed to represent a novel subtype of nasopharyngeal adenocarcinoma. In addition to being of diagnostic relevance, this fusion may ultimately represent a potential therapeutic target.     

Fallopian tube precursors of ovarian low‐ and high‐grade serous neoplasms

Traditionally, it was thought that ovarian high‐grade serous carcinoma arises from the ovarian surface epithelium and epithelial inclusion glands and that the pathogenesis is de novo; nonetheless, a convincing precursor in the ovary or peritoneum has not been identified to date. During the last few years, however, there has been a dramatic shift in thinking, and a candidate precursor is now recognized in the fallopian tube, especially within the fimbriated end – serous tubal intra‐epithelial carcinoma (STIC). Accordingly, STIC is probably the earliest histologically recognizable lesion in the pathogenesis of high‐grade serous carcinoma, but steps in this pathway which precede STIC have also been proposed. With subsequent progression, STIC implants onto the ovary and then develops into an invasive high‐grade serous carcinoma with rapid tumour growth. For invasive low‐grade serous carcinoma, it is well‐established that its pathogenesis begins with serous cystadenoma/adenofibroma, which develops sequentially into atypical proliferative serous tumour (typical serous borderline tumour), non‐invasive micropapillary (low‐grade) serous carcinoma (micropapillary serous borderline tumour) and then invasive low‐grade serous carcinoma in a relatively slow stepwise process. It is presumed that cystadenoma/adenofibroma arises from epithelial inclusion glands in the ovary, but recent evidence suggests that epithelial inclusion glands originate in the fallopian tube. Alternatively, it has been proposed that the other early precursors in the low‐grade pathway, including serous borderline tumours, non‐invasive implants and endosalpingiosis, may also arise directly from tubal mucosa. Therefore, the precursor of most ovarian high‐grade serous carcinomas originates in the fallopian tube, and that for low‐grade serous tumours may also be derived from the tube. This review paper provides an overview of the fallopian tube's potential role in the pathogenesis of both types of serous neoplasms of the ovary.     

Fine‐needle aspiration cytology and immunohistology of low‐grade adenosquamous carcinoma of the breast

Low‐grade adenosquamous carcinoma of the breast (LASCB) is a relatively recently‐described, rare histotype of breast cancer that has a favorable prognosis. Its principal microscopic features are the presence of “syringoid” (“tadpole”‐shaped) ductal profiles of tumor cells, a bland and modestly cellular stromal background, and the variable presence of keratinizing (“epidermoid”) cell groups. As such, the basic image of LASCB is quite similar to that of microcystic adnexal or adenosquamous carcinoma of the skin or “syringomatous adenoma” of the nipple. We report the fine‐needle aspiration cytologic (FNA) attributes of this neoplasm, as well as its immunohistochemical characteristics and differential diagnosis. Diagn. Cytopathol. 1999;20:13–18. © 1999 Wiley‐Liss, Inc.     

Genetic characterization of T‐PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker

T‐cell prolymphocytic leukemia (T‐PLL) is a rare post‐thymic T‐cell neoplasm with aggressive clinical course and short overall survival. So far, due to the rareness of this disease, genetic data are available only from individual cases or small cohorts. In our study, we aimed at performing a comprehensive cytogenetic and molecular genetic characterization of T‐PLL comprising the largest cohort of patients with T‐PLL analyzed so far, including correlations between the respective markers and their impact on prognosis. Genetic abnormalities were found in all 51 cases with T‐PLL, most frequently involving the TCRA/D locus (86%). Deletions were detected for ATM (69%) and TP53 (31%), whereas i(8)(q10) was observed in 61% of cases. Mutations in ATM, TP53, JAK1, and JAK3 were detected in 73, 14, 6, and 21% of patients, respectively. Additionally, BCOR mutations were observed for the first time in a lymphoid malignancy (8%). Two distinct genetic subgroups of T‐PLL were identified: A large subset (86% of patients) showed abnormalities involving the TCRA/D locus activating the proto‐oncogenes TCL1 or MTCP1, while the second group was characterized by a high frequency of TP53 mutations (4/7 cases). Further, analyses of overall survival identified JAK3 mutations as important prognostic marker, showing a significant negative impact. © 2015 Wiley Periodicals, Inc.     

Genetic characterization of HHV‐8/KSHV–positive primary effusion lymphoma reveals frequent mutations of BCL6: Implications for disease pathogenesis and histogenesis

Human herpesvirus‐8/Kaposi sarcoma‐associated herpesvirus–positive primary effusion lymphoma (PEL) is a recently identified B‐cell non‐Hodgkin lymphoma category characterized by liquid growth in the serous body cavities. Apart from viral infection, no genetic alteration is known to be associated with PEL and no recurrent cytogenetic abnormality has been identified in these lymphomas. Yet the consistent monoclonality of PEL indicates that the disease is not solely a virus‐driven proliferation. Here we report that PEL is associated with a high frequency of mutations of BCL6 5' noncoding regions, and we identify karyotypic abnormalities that may be recurrently involved in these lymphomas. Mutations of BCL‐6 5' noncoding regions occurred in 8/13 PEL. Mutations occurred in the absence of BCL6 gross rearrangements were often multiple in the same patient (7/8 mutated cases), and occurred in both HIV‐positive and HIV‐negative individuals. Since BCL6 mutations are regarded as a genetic marker of B‐cell transition through the germinal center (GC), these data are consistent with histogenetic derivation of PEL from GC or post‐GC B‐cells. Cytogenetic and FISH analysis of seven PEL cell lines showed frequent occurrence of complete or partial trisomy 12 (7/7 cases), trisomy 7 (4/7 cases), and abnormalities of bands 1q21–25 (5/7 cases). Genes Chromosomes Cancer 24:16–23, 1999. © 1999 Wiley‐Liss, Inc.     

Intravoxel water diffusion heterogeneity imaging of human high‐grade gliomas

This study aimed to determine the potential value of intravoxel water diffusion heterogeneity imaging for brain tumor characterization and evaluation of high‐grade gliomas, by comparing an established heterogeneity index (α value) measured in human high‐grade gliomas to those of normal appearing white and grey matter landmarks. Twenty patients with high‐grade gliomas prospectively underwent diffusion‐weighted magnetic resonance imaging using multiple b‐values. The stretched‐exponential model was used to generate α and distributed diffusion coefficient (DDC) maps. The α values and DDCs of the tumor and contralateral anatomic landmarks were measured in each patient. Differences between α values of tumors and landmark tissues were assessed using paired t‐tests. Correlation between tumor α and tumor DDC was assessed using Pearson's correlation coefficient. Mean α of tumors was significantly lower than that of contralateral frontal white matter (p = 0.0249), basal ganglia (p < 0.0001), cortical grey matter (p < 0.0001), and centrum semiovale (p = 0.0497). Correlation between tumor α and tumor DDC was strongly negative (Pearson correlation coefficient, ?0.8493; p < 0.0001). The heterogeneity index α of human high‐grade gliomas is significantly different from those of normal brain structures, which potentially offers a new method for evaluating brain tumors. The observed negative correlation between tumor α and tumor DDC requires further investigation. Copyright © 2009 John Wiley & Sons, Ltd.     

Controlling chronic low‐grade inflammation to improve follicle development and survival

Chronic low‐grade inflammation is one cause of follicle development disturbance. Chronic inflammation exists in pathological conditions such as premature ovarian failure, physiological aging of the ovaries, and polycystic ovary syndrome. Inflammation of the whole body can affect oocytes via the follicle microenvironment, oxidative stress, and GM‐CSF. Many substances without toxic side‐effects extracted from natural organisms have gradually gained researchers’ attention. Recently, chitosan oligosaccharide, resveratrol, anthocyanin, and melatonin have been found to contribute to an improvement in inflammation. This review discusses the interrelationships between chronic low‐grade inflammation and follicle development, the underlying mechanisms, and methods that may improve follicle development by controlling the level of chronic low‐grade inflammation.     

Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers

Microsatellite instability (MSI) is a hallmark of hereditary nonpolyposis colorectal cancer, and in these patients, results from inherited defects in DNA mismatch repair genes, mostly MSH2 and MLH1. MSI also occurs in 15% of sporadic colorectal cancers, but in these tumors, its basis is less well characterized. We investigated 46 sporadic MSI+ colorectal cancers for changes in MSH2 and MLH1 protein expression, followed by the analysis of somatic mutation, loss of heterozygosity (LOH), and promoter hypermethylation as possible underlying defects. Most cases (36/46, 78%) showed lost or reduced MLH1 expression. Among these, a majority (83%) was associated with MLH1 promoter hypermethylation, whereas the rates of LOH and somatic mutation of MLH1 were 24% and 13%, respectively. Hypermethylation and LOH were inversely correlated, suggesting that they had alternative functions in the inactivation of MLH1. MSH2 expression was lost in 7/46 (15%), and of these, 2 (29%) showed LOH and/or somatic mutation of MSH2. We conclude that most sporadic MSI+ colorectal cancers have an MLH1-associated etiology and that epigenetic modification is a major mechanism of MLH1 inactivation. Moreover, we found a significantly lower prevalence for MLH1 promoter hypermethylation in hereditary nonpolyposis colorectal cancer tumors with MLH1 germline mutations (12/26, 46%), which might explain some differences that are known to occur in the clinicopathological characteristics and tumorigenic pathways between sporadic and hereditary MSI+ colorectal cancers.     

Genetic and epigenetic regulation of IgH gene assembly

Precursor B cells assemble a diverse repertoire of immunoglobulin (Ig) genes by the process of V(D)J recombination. Assembly of IgH genes is regulated in a tissue- and stage-specific manner via the activation and then the inactivation of distinct regions within the one megabase IgH locus. Recent studies have shown that regional control is achieved using a combination of genetic and epigenetic strategies, which modulate chromatin accessibility to V(D)J recombinase, relocate IgH loci within the nucleus, and promote changes in locus conformation that alter the spatial proximity of target gene segments. Orchestration of these regulatory processes is crucial for the generation of a functional B cell repertoire.     

Colonic low‐grade endometrial stromal sarcoma and orthotopic endometrial stromal tumor with limited infiltration sharing the JAZF1‐SUZ12 gene fusion

Endometrial stromal tumors (ESTs) are composed of cells resembling endometrial stroma, and are divided into benign and malignant types based on morphology. Endometrial stromal nodule (ESN) is a benign localized tumor, and endometrial stromal sarcoma (ESS) is an infiltrative and potentially metastatic neoplasm. A series of genetic aberrations contribute to pathological diagnosis of ESTs. At present, subsets of ESN and ESS‐low grade (ESS‐LG) are characterized as JAZF1‐SUZ12/JJAZ1 gene fusion. The ESTs that show higher grade atypia but lack nuclear pleomorphism include YWHAE‐FAM22 ESS. Here we report an unusual case of ESTs. Sudden colonic perforation occurred to the patient, and emergency surgery was performed. Pathological findings suggested metastatic ESS. Thorough medical examination of the genital organs detected a 1 cm‐sized well‐demarcated uterine tumor. Microscopically, the tumor lacked infiltrative features, conforming to the definition of ESN. Both lesions demonstrated identical cytology and shared JAZF1‐SUZ12 gene fusion. Endometriosis was not found in any areas of the resected organs, strongly suggesting that the uterine orthotopic tumor metastasized. The current case uncovered the problems of differential diagnosis between ESN and ESS‐LG. We demonstrate detailed pathological features of the two lesions, and discuss the possibility of orthotopic EST with limited infiltration to develop into ESS‐LG.     

No association between rs6897932 in the gene encoding interleukin‐7 receptor α and low‐grade inflammation or self‐reported health – results from the Danish Blood Donor Study

The T‐allele in the single nucleotide polymorphism rs6897932 in the gene encoding the IL‐7 receptor α (IL7RA) is associated with reduced risk of autoimmune diseases including multiple sclerosis and also affects the course of HIV infection. Low‐grade inflammation (LGI) and self‐reported, health‐related quality of life (HRQL) are often associated with chronic diseases and widely used in assessing and monitoring health status. The aim of the present study was to evaluate whether the T‐allele in rs6897932 is associated with reduced risk of LGI (hsCRP 3–10 mg/L), history of infectious mononucleosis (IM), and HRQL in healthy individuals. A total of 17, 293 healthy Danish individuals from the Danish Blood Donor Study were included in the analyses. We tested rs6897932 as a predictor of LGI, self‐reported IM, and HRQL in univariable and multivariable models stratified by sex. No associations between rs6897932 and LGI, self‐reported IM or HRQL were found in men or women. This suggests that rs6897932 is not associated with general inflammation, and the reported associations between the T‐allele in rs6897932 with several autoimmune diseases may be mediated through effects on a restricted part of the immune system.     

Relationship between focal cortical dysplasia and epilepsy‐associated low‐grade tumors: an immunohistochemical study

We retrospectively analyzed 29 seizure‐associated temporal lobe low‐grade tumors to evaluate the utility of CD34 and bcl‐2 expression in clarifying the relationship of these tumors with different classes of focal cortical dysplasia (FCD). CD34 immunostained 75% of gangliogliomas (GG) and 60% of pleomorphic xanthoastrocytomas. FCD type IIIb [i.e. abnormal cortical layering associated with a glioneuronal tumor, according to the new International League Against Epilepsy (ILAE) classification] presented CD34‐immunopositive cells in 2/9 (22.2%) cases, whereas FCD type II in 6/7 (85.7%) cases, a difference statistically significant (p = 0.0117). Bcl‐2 immunostained 9/12 (75%) gangliogliomas and 2/3 (66.6%) gangliocytomas. The cases of FCD type IIIb resulted negative for Bcl‐2, whereas 4/7 cases (57.1%) of FCD type II showed immunopositive cells. These differences in Bcl‐2 expression between FCD type IIIb and FCD type II resulted statistically significant (p = 0.0088). Abnormal cortical layering, overall, represents the kind of FCD more commonly associated with seizure‐related low‐grade tumors, whereas FCD type II is more frequently associated with GG. The profile of CD34 and Bcl‐2 expression exhibited by GG is more similar to that observed in FCD type II. Such immunoprofile suggests the existence of a common pathogenesis linking glioneuronal tumors and FCD type II.     

The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low‐grade gliomas and glioneuronal tumors

The 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System reflects the discovery of genetic alterations underlying many central nervous system (CNS) neoplasms. Insights gained from technologic advances and novel applications in molecular diagnostics, including next‐generation sequencing and DNA methylation‐based profiling, coupled with the recognition of clinicopathologic correlates, have prompted substantial changes to CNS tumor classification; this is particularly true for pediatric low‐grade gliomas and glioneuronal tumors (pLGG/GNTs). The 2021 WHO now classifies gliomas, glioneuronal tumors and neuronal tumors into 6 families, three of which encompass pLGG/LGNTs: “Pediatric type diffuse low‐grade gliomas,” “circumscribed astrocytic gliomas,” and “glioneuronal and neuronal tumors.” Among these are six newly recognized tumor types: “diffuse astrocytoma, MYB or MYBL1‐altered”; “polymorphous low grade neuroepithelial tumor of the young (PLNTY)”; “diffuse low‐grade glioma‐MAPK altered”; “Diffuse glioneuronal tumor with oligodendroglioma‐like features and nuclear clusters (DGONC)”; “myxoid glioneuronal tumor (MGT)”; and “multinodular and vacuolating neuronal tumor (MVNT).” We review these newly recognized entities in the context of general changes to the WHO schema, discuss implications of the new classification for treatment of pLGG/LGNT, and consider strategies for molecular testing and interpretation.