Distinct Histological Types Research Articles

A CASE SERIES ON MENINGIOMA BASED ON WHO GRADING SYSTEM

Background:The dura mater, arachnoid mater and pia mater are layers of meninges surrounding brain and spinal cord. Meningiomas are tumors arising from them.These are heterogeneous group of tumors and are have 14 distinct histologic types and 03 grades of malignancy.We have studied the variants of meningiomas, as early detection helps in the treatment and improves quality of life. Objectives: -Study the histological types as per WHO grading system 2016 for meningiomas. -Differentiate the benign and malignant meningiomas on histopathology. Methods: The study is carried out in the department of pathology, D.Y. Patil medical college and hospital kolhapur from June 2020 to June 2021. Total 19 intracranial tumors were received. Sections were stained with H&E and IHC was done wherever necessary. Results:We had total 19 patients with tumors in different locations of brain. Mainly parasagital followed by intradural . Age range was 32 to 70 years with female predominance. Common histological subtypes were meningothelial (5 cases) and fibrous (5 cases), followed by transitional and angiomatous (2 cases each) and psamomatous (1 case) - WHO grade I tumors. Clear cell and atypical - grade II. Papillary, anaplastic variant - grade III. Conclusion: Meningiomas are slow growing tumors arising from the meningothelial cells. Commonly they are benign WHO grade I with female predominance. Early detection helps in the treatment and improves quality of life.

The Evolution of Ovarian Carcinoma Subclassification.

Simple SummaryHistorically, cancers presenting with their main tumor mass in the ovary have been classified as ovarian carcinomas (a concise term for epithelial ovarian cancer) and treated with a one-size-fits-all approach. Over the last two decades, a growing molecular understanding established that ovarian carcinomas consist of several distinct histologic types, which practically represent different diseases. Further research is now delineating several molecular subtypes within each histotype. This histotype/molecular subtype subclassification provides a framework of grouping tumors based on molecular similarities for research, clinical trial inclusion and future patient management.The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas.

Molecular analysis of TCGA breast cancer histologic types

Breast cancer is classified into multiple distinct histologic types, and many of the rarer types have limited characterization. Here, we extend The Cancer Genome Atlas Breast Cancer (TCGA-BRCA) dataset with additional histologic type annotations, in a total of 1063 breast cancers. We analyze this extended dataset to define transcriptomic and genomic profiles of six rare special histologic types: cribriform, micropapillary, mucinous, papillary, metaplastic, and invasive carcinoma with medullary pattern. We show the broader applicability of our constructed special histologic type gene signatures in the TCGA Pan-Cancer Atlas dataset with a predictive model that detects mucinous histologic type across cancers of other organ systems. Using a normal mammary cell differentiation score analysis, we order histologic types into a continuum from stem cell-like to luminal progenitor-like to mature luminal-like. Finally, we classify TCGA-BRCA into 12 consensus groups based on integrated genomic and histological features. We present a rich openly accessible resource of histologic and genomic characterization of TCGA-BRCA to enable studies of the range of breast cancers.

Spectrum of imaging manifestations of tumour recurrences in orthotopic neobladder.

Continent diversion with orthotopic neobladder is the most upcoming form of urinary diversion postradical cystectomy. This allows patients to void through the native urethra preserving the maximal quality of life. These patients with greater life expectancies increasingly present with a wide range of late complications, which also include local recurrences involving neobladder. Such presentations on surveillance scans can be challenging for radiologists unfamiliar with expected post-surgical anatomy and usual sites of local recurrences. Tumour in neobladder, although rare, has predilection concerning specific sites of involvement and few distinct histological types. Major subtypes of such recurrences with corresponding radiological features on multimodality imaging have been discussed in this article. Management of such cases with revision of diversions is challenging, and surgeons expect a meticulous read of such scans before contemplating pelvic clearance and secondary diversions. This pictorial review aims to appraise the literature related to various primary and secondary types of tumours involving reservoir and anastomotic sites in an orthotopic neobladder, their relative incidences and illustrate salient imaging points with case examples.

PCN5 EARLY-Onset Colorectal Cancer in the United States: A Narrative Review of the Evidence

The incidence and mortality of early-onset (<50 years of age) colorectal cancer (EOCRC) in comparison to colorectal cancer in patients greater than 50 years of age is steadily rising. Due to a delay in screening, younger populations are susceptible to later staged diagnoses, more aggressive treatment strategies, adverse histologic features, and increased mortality. This study summarizes the evidence on early-onset CRC screening, diagnosis, treatment, and survival in the United States MEDLINE, the Cochrane Library, and Google Scholar were searched for English language publications describing studies on early-onset CRC. A study was eligible for inclusion if it reported information on CRC or EOCRC incidence, screening, survival, risk factors, pathophysiology, clinical characteristics, genetic features, diagnostic criteria, treatment strategy or evaluation, racial, geographic, and socioeconomic disparities, and was published in English between January 2000 and October 2020. Patients diagnosed with EOCRC tend to have a distinct histological type including poorly differentiated tumors and signet cells, making diagnosis and treatment more difficult. Genetic features such as hereditary syndromes can contribute to EOCRC, but do not account for the majority of cases. Over-treatment patterns of young adults with EOCRC were observed. EOCRC patients that were over-treated were not shown to have greater survival rates. Ethnic minorities and low socioeconomic classes, especially African-Americans (AA), had greater mortality rates and under-treatment patterns. EOCRC incidence and mortality rates are rising rapidly, and many young adults are not being treated appropriately. Young patients have a greater likelihood of being over-treated and/or misdiagnosed, leading to long-term toxicity effects and decreased quality of life. Special attention needs to be addressed to young AA adults, to counter the observed trend, as they have the highest incidence of CRC among young population groups by race/ethnicity.

Presence of BRCA1 Gene Mutation in Bitches with Malignant Mammary Tumors

Background: Mammary tumors (MTs) in bitches are similar to breast cancers in women. Thus, they can be used as a model for human breast cancer and findings can be extrapolated for use in human medicine. BRCA1 is a tumor suppressor gene. When the gene has a mutation, it cannot repair damaged DNA, which causes genetic instability and tumorigenesis. Therefore, we aimed to study the frequency of single nucleotide polymorphisms (SNPs) in the BRCA1 gene that are associated with distinct histological types of malignant MT in bitches.Materials, Methods &amp; Results: The study population consisted of 91 bitches, including a control group of 6 animals with healthy mammary glands and 85 animals with MTs. All animals underwent a presurgery evaluation consisting of a questionnaire administered to the person responsible for the animal, a physical examination, collection of peripheral blood for hematological and serum biochemistry evaluations, an electrocardiogram, and a preanesthesia evaluation. In addition, distant metastasis was studied via chest radiography and abdominal ultrasound. After evaluations were complete, the animals that could undergo surgery were administered general anesthesia and underwent a mastectomy or mammary gland sample collection. Histopathological examination and molecular analysis were performed to identify mutations in the BRCA1 gene. Histopathological examinations found 10 different types of malignant tumors in 36 sick animals. Tumor samples plus samples from the 6 control animals were subjected to DNA extraction, polymerase chain reaction (PCR) analysis, and genetic sequencing. The tumor with the highest incidence (33.33%) was a complex carcinoma, followed by carcinoma in mixed tumor (13.88), tubular carcinoma (13.88) and carcinosarcoma (13.88). Molecular analysis revealed 3 different SNP points in 5 samples (4006G&gt;A, 3619A&gt;G, and 3761C&gt;T). The allelic variant 4006G&gt;A (1/36) resulted in the alteration of the amino acid valine by isoleucine (V1336 I). The mutation 3619A&gt;G (2/36) inserted the amino acid alanine instead of threonine (T1207 A). The mutation 3761C&gt;T (2/36) led to the alteration of the amino acid serine by phenylalanine (S1254 F), a mutation for which there are no published reports. The histological types that showed BRCA1mutations were complex carcinoma (1/5), carcinoma in mixed tumor (1/5), papillary carcinoma (1/5) and tubular carcinoma (2/5). Software analysis identified the new SNP (nucleotide 3761) in BRCA1 and 2 points mutations in nucleotides 4006 and 3619 and responsible for genetic instability.Discussion: The development of breast cancer is caused by many endogenous and exogenous factors. The results of our study show that these factors have a greater presence in female, mixed breed, uncastrated, and older dogs, confirming the data in the veterinary literature. In the present study, we found different histological types of malignant breast tumors with mutations in the BRCA1 gene, as other authors have reported. However, we also found the mutation 3761C&gt;T, which, to the best of our knowledge, has not been reported in the literature. This shows the need for studies in veterinary medicine that assess mutations in the BRCA1 gene and the most common histological types. In conclusion, SNPs in the BRCA1 gene cause genetic instability, resulting in additional mutations that lead to the development of breast tumors. They are point mutations that affect transcription, resulting in truncated proteins. These proteins may have a loss of function, leading to carcinogenesis.Keywords: polymorphism, BRCA1 gene, cancer, dogs.Descritores:polimorfismo, gene BRCA1, câncer, cães. Título: Presença da mutação do gene BRCA1 em cadelas com tumores mamários malignos.

Early Occurrence of Two Distinct Histological Types of Renal Cell Carcinoma in End-Stage Renal Disease Patient on Haemodialysis

Background: The occurrence of renal cell carcinoma is a well-known complication in end-stage renal disease on haemodialysis. Various histological types of renal cell carcinomas are observed in these patients and varies with the duration of haemodialysis. Though the synchronous association of two renal cell carcinomas in the patients are known, the existence of such dual renal tumours in the patient on dialysis is extremely rare and unheard in the English literature. Moreover, tubulocystic renal cell carcinoma is rarely reported in this setting.&#x0D; Case report and Discussion: We describe an unusual early synchronous occurrence of two tumours with distinct histology i.e. Papillary renal cell carcinoma (PRCC, type I) and Tubulocystic renal cell carcinoma (TC-RCC) in a patient with end-stage renal disease on haemodialysis for a duration less than a year. Though exact etiological factors peculiar to the occurrence of these tumours are not known, increased oxidative stress occurring in end-stage renal disease patient on haemodialysis might play an important role in carcinogenesis.&#x0D; Conclusion: Renal cell carcinoma with more than one histological type may occur exceedingly early without any symptoms in these patients. Radiologists and urologists should be aware of it for early diagnosis and prompt treatment. Pathologists should also be more cautious while grossing and pick the sub-centimetric primary or secondary tumours that may have an impact on patient survival.

Pathology of clear cell carcinoma of the ovary: A basic view based on cultured cells and modern view from comprehensive approaches.

Clear cell carcinoma (CCC) is a distinct histologic type of ovarian carcinoma. CCC is more frequent in Japan than in the Western world. CCC is chemo-resistant and often associated with paraneoplastic thromboembolism. Histologically, CCC is characterized by both cancer cells and stromas, being concordant with the cytological features. Clear cells contain abundant glycogen. Hepatocyte nuclear factor-1β is a specific marker of CCC, and is likely to be involved in glucose metabolism. Extracellular matrix (ECM)-deposited stroma and plasma cell-rich inflammatory stroma are characteristic stromas of CCC. Studies using CCC cell lines showed that CCC cells produce ECMs and stimulate plasma cell differentiation in a paracrine manner. Most CCCs, as well as endometrioid carcinomas, originate from ovarian endometriosis. This is supported by molecular genetic data, although it remains unclear why different histologic types originate from the same precursor. CCC and endometrioid carcinoma are Lynch syndrome-associated ovarian carcinomas. Recent comprehensive studies indicate that CCC is distinct not only in terms of histology but also in genomics, epigenomics and transcriptomics. This review summarizes the pathology of ovarian CCC along with a basic view based on cultured cells, and refers to recent genetic and omic data.

Cancer genomics of lung cancer including malignant mesothelioma: A brief overview of current status and future prospects.

Cancer as a genetic disease is by now well recognized. Genomic analysis of cancer cells, therefore, has greatly enhanced our ability to identify genetic alterations associated with various cancer types, including both lympho-hematopoietic as well as solid tumors. Chronic myeloid leukemia (CML), based on the specific diagnostic genetic abnormality has served as a prototype disease to clearly demonstrate the significance of the genomic analysis of cancer in identifying targeted therapy. Such a success has provided extra ordinary opportunities to investigate the role of genetic abnormalities and the pathways amenable to targeted therapy, not only in blood cancers but solid tumors such as Lung, Brain, Colon, Renal, Breast cancers as well as other epithelial and mesenchymal tumors. The main focus of this presentation is to illustrate the role of genomic analysis in targeting lung cancer, based on abnormalities or the pathways deregulated in tumor cells from individual patients. Lung cancer is one of the most common epithelial cancers associated with chronic inflammation due to cigarette smoking and other environmental carcinogens, and includes four distinct histologic type; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC) and squamous cell lung cancer. According to current estimates, 1.3 million cases of lung cancer are expected to be diagnosed worldwide annually, resulting in one million deaths. Since the discovery that patient's tumors with specific mutations in the EGFR may be sensitive to targeted therapeutic approach and the subsequent realization that the such mutations in the gene are not as prevalent, several cancer centers including ours initiated intense efforts to find other mutations or genomic alterations, which may serve as targets of specific therapy. Such efforts have successfully resulted in a battery of genes such as KRAS, ALK, C-MET, HER-2/neu, ROS1, etc., which have helped oncologists to triage the patients for personalized therapies. A significant proportion of patients with lung cancer, however, do not show any of the above genetic abnormalities. Approximately 90% of lung cancers exhibit RB1 mutation/deletion and or KRAS mutations, therefore, the signaling pathways, which regulate multistep tumorigenesis in lung cancer, are important for the treatment of histologic subtypes of lung cancer, which includes NSCLC & SCLC. Equally important was the findings that similar signaling pathways are also shared by other solid tumor types. We have investigated the role of these pathways to target these cancers and develop new strategies to treat lung, brain and related cancers. In addition, our translational studies in other tumor types such as NF2 related malignancies, specifically, Malignant Mesothelioma (MM), in which NF2 related pathway amenable to targeted therapies was identified. Selected examples representing experimental approaches will be discussed to illustrate the critical role of translational research in developing novel therapeutics for the successful and durable responses in some of these cancer types.

Immune gene signature delineates a subclass of thyroid cancer with unfavorable clinical outcomes.

Thyroid cancer (THCA) is a heterogeneous disease with multiple clinical outcomes Immune cells regulate its progression. Three immunomolecular subtypes (C1, C2, C3) were identified in gene expression data sets from TCGA and GEO databases. Among them, subtype C3 had highest frequency of BRAF mutations, lowest frequency of RAS mutations, highest mutation load and shorter progression-free survival. Functional enrichment analysis for the genes revealed that C1 was up-regulated in the ERK cascade pathway, C2 was up-regulated in cell migration and proliferation pathways, while C3 was enriched in body fluid, protein regulation and response to steroid hormones functions. Notably, the three molecular subtypes exhibit differences in immune microenvironments as shown by timer database and analysis of immune expression signatures. The abundance of B_cell, CD4_Tcell, Neutrophil, Macrophage and Dendritic cells in C2 subtype were lower than in C1 and C3 subtypes Leukocyte fraction, proliferation macrophage regulation, lymphocyte infiltration, IFN gamma response and TGF beta response scores were significantly higher in C3 compared with C1 and C2 subtypes. Unlike C3 subtype, it was observed that C1 and C2 subtypes were significantly negatively correlated with most immune checkpoint genes in two different cohorts. The characteristic genes were differentially expressed between cancer cells, adjacent tissues, and metastatic tissues in different cohorts. In summary, THCA can be subclassified into three molecular subtypes with distinct histological types, genetic and transcriptional phenotypes, all of which have potential clinical implications.

Surgical management of anterior skull-base malignancies (endoscopic vs. craniofacial resection)

Anterior skull base (ASB) malignancies are rare entities characterized by delayed diagnosis and comprise a variety of distinct histological types. Their treatment involves clinical and surgical management, with the latter encompassing open and, more recently, endoscopic approaches. The craniofacial resection, as an open approach, has revolutionized the treatment of such diseases and is the gold standard, although significant morbidity and facial scars are a shortcoming. Seeking a less invasive alternative, many surgeons have approached these pathologies using the endoscopic endonasal approach, with the theoretical advantage of reduced morbidity and no facial scars. In this manuscript, we aim to review the current state-of-art in the surgical management of the ASB malignancies. As such, indications, limitations and future perspectives of different surgical techniques are discussed.

Multi-regional sequencing reveals clonal and polyclonal seeding from primary tumor to metastases in advanced gastric cancer.

Tumor metastases to lymph nodes and distant organs are associated with worse prognosis in gastric cancer. However, little is known about the genetic profiles, subclonal architecture, and evolutional processes across primary tumors and metastases. We analyzed the genetic alterations of 106 multiregional samples including primary tumors, lymph node metastases, and visceral metastases from 10 patients with advanced gastric cancer. Histologically different portions were obtained by laser-capture microdissection. We reconstructed the subclonal architectures and inferred the primary to lymph or visceral metastatic seeding patterns. The different histological portions in primary tumors had common mutations, suggesting common ancestral tumor origins transformed into distinct histological types. In almost all cases, TP53 mutations were identified as clonal mutations across primary tumors and metastases. Subclonal reconstruction and phylogenetic analysis showed primary tumors were classified into monoclonal or polyclonal tumors. All monoclonal primary tumors disseminated as metastases with the same tumor composition (100%, 26/26 samples). In contrast, polyclonal primary tumors mainly spread as metastases by way of polyclonal seeding (84%: 37/44 samples). Clonal mutations were maintained at both the primary and metastatic sites and genetic divergence of these was low. These findings shed light on the genetic basis of primary tumor dissemination and metastatic processes in advanced gastric cancer.

Large tumor size is a poor prognostic factor of gastric cancer with signet ring cell: Results from the surveillance, epidemiology, and end results database.

There has been a steady increase in the incidence of signet ring cell (SRC) carcinoma, a distinct histological type with cells containing abundant intracytoplasmic mucin. We aimed to analyze the clinicopathological characteristics and prognostic value of patients with SRC gastric cancer (GC) who underwent gastrectomy.Clinical data of 10,312 GC patients who underwent D2 radical gastrectomy were obtained from the Surveillance, Epidemiology, and End Results database and were retrospectively analyzed. X-tile plots were constructed to illustrate the optimal cut-off points using the minimum P-value from the log-rank Chi-squared test. The Kaplan–Meier method was used for the analysis of the overall cumulative probability of survival. Their differences were evaluated using the log-rank test. The Cox multiple factors analysis was performed using the logistic regression method.In total, 946 (9.17%) SRC GC patients with pT1a-4bN0-3bM0 stage cancer were recruited. The optimal cut-off point for size was 49 mm. The 3-year overall survival (OS) rates of the SRC GC, large-size, and small-size groups were 35.89%, 30.63%, and 44.96%, respectively (P < .05). Cox multivariate analysis showed that tumor size (odds ratio [OR] = 2.032), T3 category (OR = 1.324), T4a category (OR = 1.945), and T4b category (OR = 2.163) were independent hazard prognostic factors.SRC GC has a distinct biological behavior, presents as a large-sized tumor (≥49 mm), and is associated with worse outcomes. SRC GC patients have 2.032 times risk of mortality. SRC patients with larger tumors are at higher risk for infiltrative growth, lymph node metastasis, and distant metastasis.

An Incidental Collision Tumor of the Sella Turcica

To present a case describing an incidentally discovered pituitary mass that was found to be a collision tumor containing 2 distinct histologic cell types: (1) a growth hormone (GH)-secreting pituitary adenoma, and (2) a gangliocytoma. Sellar gangliocytomas are very rare benign neuroblastic tumors that originate from the posterior pituitary. The majority are associated with pituitary adenomas. The co-existence of these 2 morphologically distinct tumors is known as a collision tumor, a rare disease entity of which the pathogenesis is not well understood. We present a case of a woman with an incidentally discovered pituitary mass that was found to be a collision tumor. A 44-year-old woman presented with an incidentally discovered pituitary mass and was found to have elevated insulin-like growth factor 1 (IGF-1) levels. The patient underwent endoscopic transsphenoidal excision of the pituitary mass. Histopathology of the tumor revealed a mixed pituitary adenoma that stained for GH and prolactin, and a gangliocytoma. Postoperatively, the patient developed temporary central adrenal insufficiency and permanent diabetes insipidus. Postoperative lab studies revealed a normal IGF-1 level, and a magnetic resonance imaging scan showed no residual or recurrent tumor. While sellar gangliocytoma is a rare lesion, when it is present, a co-existing pituitary adenoma should also be suspected. Further investigation should be done to determine the pathophysiology of these collision tumors, which could be beneficial in guiding diagnosis and treatment.

Immune Gene Signature Delineates a Subclass of Papillary Thyroid Cancer with Unfavorable Clinical Outcomes.

Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance.

Abstract 4342: Inverted sinonasal papilloma and associated carcinoma-transcriptome analysis and out-hoxing developmental genes

Abstract Introduction Sinonasal papillomas, a group of benign epithelial tumors of the sinonasal tract, are classified into 3 distinct histologic types: exophytic, endophytic and oncocytic . Associated clinical problems include a tendency towards local destruction, recurrence and malignant transformation. While controversy persists in determining the optimal therapeutic approach in a given patient, prognostic markers identifying patients who will benefit from more aggressive treatment and novel molecular targeted therapies are urgently needed. The majority of endophytic papillomas require a lengthy period for malignant transformation, but the trigger underlying the malignant changes remains obscure. The present study aimed to identify underlying mechanisms in the malignant transformation of sinonasal inverted papillomas using RNA seq. Material and methods Samples from 36 consecutive patients formed the study material and were microdisected from FFPE. Pools of RNA were subjected to expression profiling using whole-transcriptome shotgun sequencing. For validation, differentially expressed candidates were analyzed by IHC. Results The studied cohort showed a continuum, with 14 sinonasal papilloma (11 inverted type, 2 oncocytic and 1 exophytic type), 2 sinonasal papilloma with dysplastic changes, 3 carcinoma in situ and 17 invasive squamous cell carcinoma arising in a papillomatous background (majority being associated with inverted type papilloma). Differential gene expression profiles from 14 papillomas, 14 squamous carcinomas versus 4 normal sinonasal mucosa were generated and compared to each other. 1447 genes and noncoding transcripts were detected as differentially expressed with fold change &amp;gt;2 and false discovery rate &amp;lt; 0.035. These genes and transcripts were annotated and computationally analyzed using the Ingenuity Pathway Analysis program. The highest expressed genes and potential drivers were predominantly development- and differentiation-related genes. To validate the RNA-Seq results, we used IHC assessing the protein expression of 5 highly upregulated genes considered important. These candidate genes were HOXA9, EN1, DUX4, CA-IX, and CK5/6 with expressions at 30%, 50%, 60%, 60% and 95% respectively. Conclusion We assume that sinonasal papillomas are mainly defined by high number of overexpressed developmental/homeobox genes, which provide the potential for transformation/ plasticity, along with differentiation and proliferation behavior of neoplastic cells. The data form the basis for understanding cell fate determination and cellular homeostasis in the normal sinonasal mucosa and the contribution of different mucosal components to the etiology/ molecular pathology of sinonasal dysplasia and carcinoma. Citation Format: Achim H. Bell, Ehab Y. Hanna, Randal S. Weber, Victor G. Prieto, Diana Bell. Inverted sinonasal papilloma and associated carcinoma-transcriptome analysis and out-hoxing developmental genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4342.

Mutational landscape of goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix is distinct from typical carcinoids and colorectal adenocarcinomas

AbstractThere is limited data on the spectrum of molecular alterations in goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix. We used next generation sequencing to determine mutations of potential pathogenetic and therapeutic significance in this rare group of tumors. Adequate DNA was successfully extracted in 34/46 cases and the final group included 18 goblet cell carcinoids and 16 adenocarcinoma ex goblet cell carcinoids. Illumina TruSeq™ was used for sequencing exons of a custom 282 gene panel using an Illumina HiSeq 2000. All cases had a minimum coverage depth of at least 50 reads. After filtering through the Exome Sequencing Project, the number of mutations per case ranged from 0–9 (mean:3). The mutational burden in adenocarcinoma ex goblet cell carcinoids was significantly higher than goblet cell carcinoids (mean 5 vs. 3; p < 0.05) but the spectrum of alterations overlapped between the two groups. The most frequent mutations included ARID1A (4/34), ARID2 (4/34), CDH1 (4/34), RHPN2 (4/34), and MLL2 (3/34). Some mutations typically seen in conventional colorectal adenocarcinomas were also identified but with much lower frequency (APC :4/34; KRAS :2/34). MLL2 and KRAS mutations were only seen in adenocarcinoma ex goblet cell carcinoids and TP53 mutations were limited to poorly differentiated adenocarcinoma ex goblet cell carcinoids (2/34). Copy number changes could be evaluated in 15/34 cases and showed low copy number gains in CDKN1B (6/15) and NFKBIA (6/15), among others. The overlapping molecular alterations suggest that goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids are best considered two grades of differentiation of the same tumor rather than two distinct histological types. Mutations in TP53, CDH1 and MLL2 mutations were predominantly present in the adenocarcinoma ex goblet cell carcinoid group consistent with transformation to a higher grade lesion. The unique mutational profile also offers an explanation for the poor chemosensitivity in these tumors and highlights the need for developing new targeted therapies.

Primary Adenocarcinoma of the Uterine Cervix: Classification and Grading

Abstract Cervical adenocarcinomas are a group of malignancies with several distinct histologic tumor types, which include endocervical usual type, endometrioid, intestinal, villoglandular, gastric, signet ring, serous, clear cell, and mesonephric. Diagnosis of cervical adenocarcinoma, in particular early diagnosis, and classification of the tumor type may pose a significant challenge. The goal of this article is to review the current classification, diagnostic criteria, adjunct markers, and differential diagnosis of various subtypes of cervical adenocarcinomas. The article presents up-to-date summary of such problematic issues as differentiating glandular tumors from benign mimics, differentiating early invasive lesions from adenocarcinoma in situ, determining the tumor type, and, finally, differentiating primary cervical adenocarcinoma from uterine endometrioid adenocarcinoma. Discussion of human papillomavirus detection in different tumor types is provided.

Protocol for the Analysis of Laser Capture Microdissected Fresh-Frozen Tissue Homogenates by Silver-Stained 1D SDS-PAGE.

The heterogeneity present in solid tumors adds significant difficulty to scientific analysis and improved understanding. Fundamentally, solid tumor formation consists of cancer cells proper along with stromal elements. The burgeoning malignant process is dependent upon modified stromal elements. Collectively, the stroma forms an essential microenvironment, which is indispensable for the survival and growth of the malignant neoplasm. This cellular heterogeneity makes molecular profiling of solid tumors via mass spectrometry (MS)-based proteomics a daunting task. Laser capture microdissection (LCM) is commonly used to obtain distinct histological cell types (e.g., tumor parenchymal cells, stromal cells) from tumor tissue and attempt to address the tumor heterogeneity interference with downstream liquid chromatography (LC) MS analysis. To provide optimal LC-MS analysis of micro-scale and/or nano-scale tissue sections, we modified and optimized a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) protocol for the LC-MS analysis of LCM-procured fresh-frozen tissue specimens. Presented is a detailed in-gel digestion protocol adjusted specifically to maximize the proteome coverage of amount-limited LCM samples, and facilitate in-depth molecular profiling. Following LCM, targeted tissue sections are further fractionated using silver-stained 1D-SDS-PAGE to resolve and visualize tissue proteins prior to in-gel digestion and subsequent LC-MS analysis.

Head and Neck Carcinoma Immunotherapy: Facts and Hopes.

Cancer of the head and neck (HNC) is a heterogeneous disease of the upper aerodigestive tract, encompassing distinct histologic types, different anatomic sites, and human papillomavirus (HPV)-positive as well as HPV-negative cancers. Advanced/recurrent HNCs have poor prognosis with low survival rates. Tumor-mediated inhibition of antitumor immune responses and a high mutational burden are common features of HNCs. Both are responsible for the successful escape of these tumors from the host immune system. HNCs evolve numerous mechanisms of evasion from immune destruction. These mechanisms are linked to genetic aberrations, so that HNCs with a high mutational load are also highly immunosuppressive. The tumor microenvironment of these cancers is populated by immune cells that are dysfunctional, inhibitory cytokines, and exosomes carrying suppressive ligands. Dysfunctional immune cells in patients with recurrent/metastatic HNC can be made effective by the delivery of immunotherapies in combination with conventional treatments. With many promising immune-based strategies available, the future of immune therapies in HNC is encouraging, especially as methods for genetic profiling and mapping the immune landscape of the tumor are being integrated into a personalized approach. Efficiency of immune therapies is expected to rapidly improve with the possibility for patients' selection based on personal immunogenomic profiles. Noninvasive biomarkers of response to therapy will be emerging as a better understanding of the various molecular signals co-opted by the tumors is gained. The emerging role of immunotherapy as a potentially beneficial addition to standard treatments for recurrent/metastatic HNC offers hope to the patients for whom no other therapeutic options exist. Clin Cancer Res; 24(1); 6-13. ©2017 AACR.