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Myoepithelial tumors are rare neoplasms that develop from myoepithelial cells in glandular structures and soft tissues. Primary intracranial myoepithelial neoplasms are even rarer with around ten cases reported. On the other hand, adrenocortical carcinoma (ACC) is also uncommon with an annual incidence of 0.7–2 per million and carries a poor prognosis. It is known to have an association with certain familial cancer syndromes. Even in sporadic cases, a significant portion of them had other malignancies before and after diagnosis of ACC. We reported a 34-year-old gentleman who was diagnosed to have ACC without known familial cancer syndrome. After that, he was also found to have right occipital myoepithelioma that was confirmed by excisional biopsy. There was no known association between these two pathologies. This is the first report of coincidence of ACC and intracranial myoepithelioma.

We report this rare case of cerebral phaeohyphomycosis in a previously healthy Chinese boy, who was found to have caspase recruitment domain family member 9 (CARD9) deficiency. Initial radiological features suggested a neoplastic cerebral lesion, while histopathological examination supplemented by internal transcribed sequencing (ITS) of cerebral tissue confirmed the diagnosis of phaeohyphomycosis. He was treated with intravenous (IV) liposomal amphotericin B and voriconazole, guided by plasma and cerebrospinal fluid (CSF) level monitoring at drug initiation. At the 1 year follow-up, the patient demonstrated near complete neurological and radiological recovery.

ObjectiveSporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs.DesignWe established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed.ResultsWe observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time.ConclusionsThese organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

ObjectiveCell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells.DesignWe explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers:ARHGAPfusions,RHOAandCDH1,in modulating CC (CCi) or CM (CMi) adhesion independence.Results97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling viaRHOAmutation orARHGAPfusions. Inducible knockout ofARHGAPfusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered withCDH1orRHOAmutations became CMi or CCi, respectively.ConclusionsThe CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

Malignant melanoma is a relatively common malignancy in the West, but has a significantly lower incidence in Asians. Stark contrast in clinicopathological characteristics and prognosis has been observed between the 2 populations, yet data are limited. Here, we evaluate 106 Asian patients from a tertiary referral center in Hong Kong during an 11-year period. The purpose of this study was to collectively review all types of melanomas to analyze the clinicopathological characteristics of this poorly understood condition in an Asian population.A total of 106 patients diagnosed with malignant melanoma from 2002 to 2012 were retrospectively reviewed. Demographics, clinical presentations, pathological subtypes, treatments, and survival outcomes were evaluated.Cutaneous melanomas dominated with 46 (43.4%) cases, followed by mucosal (39.6%), ocular (9.4%), and melanomas of unknown primary (7.5%); 43.3% patients presented in stage I, 36.7% in stage II, 18.9% in stage III, and 1.1% in stage IV. Acral lentiginous melanoma was the commonest subtype of cutaneous melanomas (60.9%). When types of melanomas were reviewed collectively, the median overall survival, disease-specific survival, and recurrence-free survival were 37, 45, and 48 months, respectively. Cutaneous melanoma had the best median overall survival of 59 months, followed by ocular melanoma (58 months), mucosal melanoma (18 months), and melanoma of unknown primary (2 months). Similar patterns were observed for disease-specific survival and recurrence-free survival.Melanoma among Asians remains poorly understood. There is a clear distinction in the clinical patterns between Asians and whites and the difference is not solely accounted for by the lower incidence of cutaneous melanoma. Certain subtypes, such as mucosal melanoma and is acral lentiginous melanoma, seemed to have disproportionately high incidences. Further studies are warranted to elucidate these observations. The poor survival outcomes reflected the need for better awareness and understanding of the condition by both the general public and the physicians.

OBJECTIVE: Serrated polyps (hyperplastic polyps, sessile or traditional serrated adenomas), which can arise in a sporadic or polyposis setting, predispose to colorectal cancer (CRC), especially those with microsatellite instability (MSI) due to MLH1 promoter methylation (MLH1(me+)). We investigate genetic alterations in the serrated polyposis pathway. DESIGN: We used a combination of exome sequencing and target gene Sanger sequencing to study serrated polyposis families, sporadic serrated polyps and CRCs, with validation by analysis of The Cancer Genome Atlas (TCGA) cohort, followed by organoid-based functional studies. RESULTS: In one out of four serrated polyposis families, we identified a germline RNF43 mutation that displayed autosomal dominant cosegregation with the serrated polyposis phenotype, along with second-hit inactivation through loss of heterozygosity or somatic mutations in all serrated polyps (16), adenomas (5) and cancer (1) examined, as well as coincidental BRAF mutation in 62.5% of the serrated polyps. Concurrently, somatic RNF43 mutations were identified in 34% of sporadic sessile/traditional serrated adenomas, but 0% of hyperplastic polyps (p=0.013). Lastly, in MSI CRCs, we found significantly more frequent RNF43 mutations in the MLH1(me+) (85%) versus MLH1(me-) (33.3%) group (p

Background Frozen section analysis (FSA) is frequently used in salvage surgery for recurrent or residual nasopharyngeal carcinoma (rNPC) after radiotherapy to ensure adequate tumor removal. However, the diagnostic accuracy of FSA in rNPC has never been clearly established. We believe that this is the first study to specifically address these issues. Methods Patients with rNPC who underwent nasopharyngectomy in Queen Mary Hospital from 2006 to 2011 were identified. Clinical data, FSA results, and permanent histological results were analyzed. Results In the tissue-based analysis, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 70.6%, 100%, 100%, 95.2%, and 95.7%, respectively. Only 37% of inconclusive FSA turned out negative on permanent histology. Presence of inconclusive (p = .000) or positive (p = .000) FSA results in the same operation significantly lowered the NPV of FSA. Conclusion FSA is useful in ensuring clear resection margins for rNPC. Further resection is advisable in cases of inconclusive FSA results. © 2013 Wiley Periodicals, Inc. Head Neck 36: 638–642, 2014

Gastric cancer is a heterogeneous disease with multiple environmental etiologies and alternative pathways of carcinogenesis. Beyond mutations in TP53, alterations in other genes or pathways account for only small subsets of the disease. We performed exome sequencing of 22 gastric cancer samples and identified previously unreported mutated genes and pathway alterations; in particular, we found genes involved in chromatin modification to be commonly mutated. A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS). The mutation spectrum for ARID1A differs between molecular subtypes of gastric cancer, and mutation prevalence is negatively associated with mutations in TP53. Clinically, ARID1A alterations were associated with better prognosis in a stage-independent manner. These results reveal the genomic landscape, and highlight the importance of chromatin remodeling, in the molecular taxonomy of gastric cancer.

SummaryWe report a 26-year-old man with 6 years, history of duodenal gastrointestinal stromal tumor (GIST) with liver, peritoneum and lung metastases. He presented with left eye ptosis, diplopia, left facial numbness and a left temporal fossa mass that was confirmed to be GIST with left skull and left orbit metastases. Craniectomy with cranioplasty, tumor excision and decompression were performed. There was an improvement of his visual symptoms and facial numbness. To our knowledge, this is one of the few reports of surgical management of GIST, metastasized to skull and orbit, with good symptomatic relief.

With recent advances in 3D organoid culture techniques, normal epithelial and tumor cells can be directly cultured from clinical specimens in vitro and expanded long-term with a very high success rate. Thus, this constitutes a good platform for various mechanistic functional studies and clinical applications. A previous karyotyping and gene expression profiling study has indicated that organoid culture of normal epithelial cells can be propagated for long periods of time without genomic alterations. However, data on the genomic stability of tumor organoids in long-term culture are not yet available. We have successfully established organoid cultures derived from either primary tumor or lymph node metastasis from 4 gastric cancer patients. For each sample, we performed long-term culture for at least 6 months. DNA was extracted from blood, as well as the early and late passages of these organoids, and submitted for whole-exome sequencing (WES), achieving a mean coverage approaching 50X. Somatic mutations detected in early versus late passage gastric cancer organoids were compared. Furthermore, we examined the organoids for copy number variations based on the coverage and loss of heterozygosity (LOH) information derived from exome sequencing. We detected between 80 to 228 somatic mutations in the 4 early passage organoids, in which over 84-99% of them were retained during long-term culture. We detected 16, 20, 31 and 98 new mutations in the 4 long-term cultures, respectively. The one case with a substantially large number of new mutations (n=98) appeared to have emerged from a subclone of TP53 wild-type cells in a TP53 mutant tumor. Notably, the C>T mutation was the most dominant mutation spectrum in this case, constituting 48%. Despite the presence of frequent long segment LOH and chromosomal aberrations in early passage organoids, indicating the presence of chromosomal instability, these patterns of aberrations were stably maintained in long-term passage. Overall, with the current organoid culture protocol, tumor genomes are mostly stably maintained with the accumulation of only a small number of new mutations. Our results indicate that this is a reliable and stable in vitro cell culture model for various cancer-related and clinical studies. Citation Format: Sarah Siu Kuen Yue, Helen Hoi Ning Yan, Hoi Cheong Siu, Siu Lun Ho, Wai Yin Tsui, Dessy Chan, Annie Shuk Yee Chan, Bernard Chi Hang Lee, Anthony Kin Wang Chan, Suet Yi Leung. Gastric cancer organoid culture shows preserved genomic stability in long-term passage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2017-4378

Primary cutaneous mucoepidermoid carcinoma (MEC) is a rare disease entity. Only around 20 cases have been reported so far. Herein, we present two cases for better understanding of the condition: A 74-year-old lady with a low-grade primary cutaneous MEC at her right external auditory ear canal was treated with surgical resection and adjuvant radiotherapy. The patient developed recurrence five months later and succumbed. Another 81-year-old lady with a high-grade primary cutaneous MEC carcinoma on her left parietal scalp treated by excisional biopsy remained disease free for 10 years. Their histological slides were discussed in details. Current evidence in the literature was also reviewed and summarized.

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.

Frozen section analysis (FSA) is frequently used in salvage surgery for recurrent or residual nasopharyngeal carcinoma (rNPC) after radiotherapy to ensure adequate tumor removal. However, the diagnostic accuracy of FSA in rNPC has never been clearly established. We believe that this is the first study to specifically address these issues.Patients with rNPC who underwent nasopharyngectomy in Queen Mary Hospital from 2006 to 2011 were identified. Clinical data, FSA results, and permanent histological results were analyzed.In the tissue-based analysis, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 70.6%, 100%, 100%, 95.2%, and 95.7%, respectively. Only 37% of inconclusive FSA turned out negative on permanent histology. Presence of inconclusive (p = .000) or positive (p = .000) FSA results in the same operation significantly lowered the NPV of FSA.FSA is useful in ensuring clear resection margins for rNPC. Further resection is advisable in cases of inconclusive FSA results.

Dear Editor, A 58-year-old man presented with bilateral, persistent steroid refractory vitritis in 2005. Repeated vitreous biopsies in 2006 and 2007 were inconclusive. In late 2008, he developed vertigo and a magnetic resonance imaging (MRI) scan showed an intra-axial infratentorial tumor with marked cerebellar edema. Brain biopsy showed diffuse large B cell lymphoma (DLCL). Systemic staging, including lumbar puncture, was negative. He was treated as combined intraocular lymphoma (IOL) and primary brain lymphoma (PBL) with chemotherapy [four courses high-dose methotrexate (MTX), rituximab, vincristine, and procarbazine] followed by whole brain radiotherapy (RT, 40 Gy) [1]. This resulted in clinical and radiological remission. Further treatment was limited by poor performance status and renal impairment. His vision remained impaired due to bilateral grade 3 posterior subcapsular cataract and grade 2 cortical cataract. Right eye phaco-emulsification with implantation of posterior chamber intraocular lens was performed in 2008 with good visual recovery. However, his left eye showed progressively decreased acuity to hand movement. An examination showed keratic precipitates, dense cataract, vitritis, retinal infiltrates, and hemorrhages. An MRI and lumbar puncture remained normal. He was treated as recurrent IOL with intrathecal (IT) MTX and cytosine arabinoside (Ara-C). Subsequent left eye cataract surgery and vitreous biopsy showed small lymphocytes but no malignant cells, but panuveitis persisted despite further anterior sub-Tenon’s triamcinolone acetonide injection. A repeat pars plana vitrectomy was performed in 2009. The histology showed large sized atypical lymphoid cells, but an immunogloubin heavy chain polymerase chain reaction study showed no clonality. In view of likely persistent IOL, additional dose-limiting conformal RT was given to both eyes (1.8 Gy/fr up to 28.2 Gy). Vision in his right eye remained good (0.5), but his left eye deteriorated to no light perception. By 2011, he developed left eye pain, florid vitritis, hypopyon, and glaucoma (40 mmHg, Fig. 1a). The painful blind eye was enucleated (Fig. 1b). The specimen showed abundant CD20 positive lymphoma cells in both chambers of the eye (Fig. 1c, d) with frequent mitotic figures and necrosis. Six months later, radiological and physical examinations showed no evidence of brain or orbital lymphoma (Fig. 1e). Fig. 1 a Left eye hypopyon (arrow) of sedimentation of lymphoma cells. b Gross specimen bisected globe with extensive amorphous white infiltrations representing the hypopyon. c Photomicrograph of anterior chamber with abundant lymphoma cell infiltration (arrows ... The related pathologies of IOL and PBL may occur concurrently or sequentially. Central nervous system (CNS) investigation and therapy are advised for apparent isolated IOL [2, 3]. Meticulous fundal examination is also mandatory for PBL patients [4]. The incidence, time sequence, and interval between the entities vary and may be related to the anatomical location of the PBL lesion [5]. Histologically, both conditions are related and extra-CNS spread is uncommon [4]. The treatment includes high dose systemic and IT MTX, Ara-C, and RT [1, 3, 6]. The long-term visual, neurological, and survival prognosis is usually guarded [4, 6]. Our patient is unique in a number of ways. Although IOL is a well-known ophthalmological masquerade lesion, a 3-year lapse between IOL and PBL without treatment is unusual. In addition, the IOL was exquisitely localized to the globe, evident by its isolated nonresponse to chemotherapy, first in both eyes and eventually only in the left eye [6]. After failing multiple maximal dose therapies, the options for a frail patient become limited [1]. The hypopyon is indicative of fulminant lymphoma in the aqueous chamber [2]. Intraocular chemotherapy injection is invasive and may breach the capsular sealing of the amorphous DLCL. It is unlikely to be effective against refractory DLCL. The role of temozolamide or intraocular rituximab is uncertain [7]. Historically, the first effective treatment of IOL was enucleation (c.f. ocular melanoma and retinoblastoma) [6]. Although relegated to a historical curiosity, IOL enucleation remerged as a novel option in our very unique case with refractory localized cells in a painful blind eye. Disease and symptom control was achieved with minimal morbidity.