Japanese Classification of Esophageal Cancer, 12th Edition: Part II.

This is the second half of English edition of Japanese Classification of Esophageal Cancer, 12th Edition that was published by the Japan Esophageal Society in 2022.

Integrated genomic characterization of oesophageal carcinoma.

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.

Genetic Profile and Functional Proteomics of Anal Squamous Cell Carcinoma: Proposal for a Molecular Classification.

Anal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.

Mapping of Lymph Node Metastasis From Esophagogastric Junction Tumors: A Prospective Nationwide Multicenter Study.

OBJECTIVE: The aim of the study was to determine the optimal extent of lymph node dissection for the 2 histological types of esophagogastric junction (EGJ) tumors based on the incidence of metastasis in a prospective nationwide multicenter study. BACKGROUND: Because most previous studies were retrospective, the optimal surgical procedure for EGJ tumors has not been standardized. METHODS: Patients with cT2-T4 adenocarcinoma or squamous cell carcinoma located within 2.0 cm of the EGJ were enrolled before surgery. Surgeons dissected all lymph nodes prespecified in the protocol, using either the abdominal transhiatal or right transthoracic approach. The primary endpoint was the metastasis rate of each lymph node. Lymph nodes were classified according to metastasis rate, as follows: category-1 (strongly recommended for dissection), rate more than 10%; category-2 (weakly recommended for dissection), rate from 5% to 10%; and category-3 (not recommended for dissection), rate less than 5%. RESULTS: Between 2014 and 2017, 1065 patients with EGJ tumor were screened, and 371 were enrolled. Among 358 patients who underwent surgical resection, category-1 nodes included abdominal stations 1, 2, 3, 7, 9, and 11p, whereas category-2 nodes included abdominal stations 8a, 19, and lower mediastinal station 110. If esophageal involvement exceeded 2.0 cm, station 110 was assigned to category-1. Among 98 patients who had either adenocarcinoma with esophageal involvement over 3.0 cm or squamous cell carcinoma, there were no category-1 nodes in the upper/middle mediastinal field, whereas category-2 nodes included upper mediastinal station 106recR and middle mediastinal station 108. When esophageal involvement exceeded 4.0 cm, station 106recR was assigned to category-1. CONCLUSION: The study accurately identified the distribution of lymph node metastases from EGJ tumors and the optimal extent of subsequent lymph node dissection.

Expression Profiles of ASIC1/2 and TRPV1/4 in Common Skin Tumors.

The acid-sensing ion channels ASIC1 and ASIC2, as well as the transient receptor potential vanilloid channels TRPV1 and TRPV4, are proton-gated cation channels that can be activated by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of ASIC1, ASIC2, TRPV1 and TRPV4 in malignant melanoma (MM), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and in nevus cell nevi (NCN). We conducted immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express ASIC1/2 and TRPV1/4. Striking results were that BCCs are often negative for ASIC2, while nearly all SCCs express this marker. Epidermal MM sometimes seem to lack ASIC1 in contrast to NCN. Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions. Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions. ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, thus being potential diagnostic and therapeutic targets.

Stratification of HPV-associated and HPV-negative oropharyngeal squamous cell carcinomas based on DNA methylation epigenotypes.

While the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing in these two decades, primarily due to human papillomavirus (HPV), stratification of OPSCC into molecular subgroups showing different clinicopathological features has not been fully investigated. We performed DNA methylome analysis using Infinium 450k for 170 OPSCC cases, including 89 cases in our cohort and 81 cases reported by The Cancer Genome Atlas, together with targeted exon sequencing analysis. We stratified OPSCC by hierarchical clustering analysis using methylome data. Methylation levels of classifier markers were validated quantitatively using pyrosequencing, and area under the curve (AUC) values of receiver operating characteristics (ROC) curves were calculated. OPSCC was stratified into four epigenotypes: HPV(+) high-methylation (OP1), HPV(+) intermediate-methylation (OP2), HPV(-) intermediate-methylation (OP3) and HPV(-) low-methylation (OP4). Ten methylation marker genes were generated: five to classify HPV(+) cases into OP1 and OP2, and five to classify HPV(-) cases into OP3 and OP4. AUC values of ROC curves were 0.969 and 0.952 for the two marker panels, respectively. While significantly higher TP53 mutation and CCND1 copy number gains were observed in HPV(-) than in HPV(+) groups (p < 0.01), no significant difference of genomic aberrations was observed between OP1 and OP2, or OP3 and OP4. The four epigenotypes showed significantly different prognosis (p = 0.0006), distinguishing the most favorable OPSCC subgroup (OP1) among generally favorable HPV(+) cases, and the most unfavorable OPSCC subgroup (OP3) among generally unfavorable HPV(-) cases. HPV(+) and HPV(-) OPSCC are further divided into distinct DNA methylation epigenotypes, showing significantly different prognosis.

The papillomavirus E5 gene does not affect EGFR transcription and overall survival in cervical cancer.

INTRODUCTION: The human papillomavirus (HPV) E5 gene encodes a small and highly hydrophobic oncoprotein that affects immune evasion, cell proliferation, loss of apoptotic capacity and angiogenesis in tumors. E5 shows an affinity for biological membranes and was associated with an increase of epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling through the accumulation of EGFR in cellular membranes. Due to the frequent integration of the HPV genome into the host cell genome, E5 is frequently not transcribed in cervical tumors. AIM: In this study we looked forward to verifying whether the potential expression of E5 protein in human papillomavirus 16 positive (HPV16+ ) and human papillomavirus 18 positive (HPV18+ ) cervical tumors was associated with levels of EGFR and vascular endothelial growth factor A (VEGFA) transcription and with patients overall survival. RESULTS: Association between the presence of E5 transcripts and viral genome disruption was observed for HPV16+ and HPV18+ tumors. Association was not observed between tumors potentially capable of translating E5 and EGFR or VEGFA transcriptional levels. Similarly, the capability of translating E5 and overall survival in patients with HPV16+ squamous cell carcinoma tumors stage ≥ IB2 were not associated. CONCLUSION: The likely presence of E5 transcripts was neither associated to a higher activity of the EGFR-VEGFA pathway nor to the overall survival of patients with HPV16+ squamous cell carcinoma in stages ≥ IB2.

Prognosis of oral squamous cell carcinoma with perineural invasion: A comparative study of classification types.

OBJECTIVE: To investigate the histological location and extent of perineural invasion (PNI) as prognostic factors. DESIGN: Retrospective review of medical records and histological analysis of 116 patients with oral squamous cell carcinoma (OSCC). SETTING: Two major public tertiary hospitals treating head and neck cancer, Royal Adelaide Hospital and Flinders Medical Centre, in South Australia. PARTICIPANTS: Patients diagnosed with OSCC who underwent primary surgical treatment with curative intent at these two centres from January 1, 2005 through December 31, 2015. MAIN OUTCOME MEASURES: The primary end points were disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: The presence of PNI as a binary factor alone did not significantly influence the clinical outcomes. Extratumoural (ET) PNI as measured from the tumour edge was associated with worse DFS on multivariate analyses. Multifocal PNI was associated with worse DFS and DSS. DFS in multifocal PNI was worse irrespective of whether adjuvant therapy was administered. CONCLUSIONS: The presence of multifocal and ET PNI in OSCC is associated with poor clinical outcomes. Patients with multifocal PNI were associated with worse DFS even with adjuvant therapy.

A qualitative transcriptional signature for the histological reclassification of lung squamous cell carcinomas and adenocarcinomas.

BACKGROUND: Targeted therapy for non-small cell lung cancer is histology dependent. However, histological classification by routine pathological assessment with hematoxylin-eosin staining and immunostaining for poorly differentiated tumors, particularly those from small biopsies, is still challenging. Additionally, the effectiveness of immunomarkers is limited by technical inconsistencies of immunostaining and lack of standardization for staining interpretation. RESULTS: Using gene expression profiles of pathologically-determined lung adenocarcinomas and squamous cell carcinomas, denoted as pADC and pSCC respectively, we developed a qualitative transcriptional signature, based on the within-sample relative gene expression orderings (REOs) of gene pairs, to distinguish ADC from SCC. The signature consists of two genes, KRT5 and AGR2, which has the stable REO pattern of KRT5 > AGR2 in pSCC and KRT5 < AGR2 in pADC. In the two test datasets with relative unambiguous NSCLC types, the apparent accuracy of the signature were 94.44 and 98.41%, respectively. In the other integrated dataset for frozen tissues, the signature reclassified 4.22% of the 805 pADC patients as SCC and 12% of the 125 pSCC patients as ADC. Similar results were observed in the clinical challenging cases, including FFPE specimens, mixed tumors, small biopsy specimens and poorly differentiated specimens. The survival analyses showed that the pADC patients reclassified as SCC had significantly shorter overall survival than the signature-confirmed pADC patients (log-rank p = 0.0123, HR = 1.89), consisting with the knowledge that SCC patients suffer poor prognoses than ADC patients. The proliferative activity, subtype-specific marker genes and consensus clustering analyses also supported the correctness of our signature. CONCLUSIONS: The non-subjective qualitative REOs signature could effectively distinguish ADC from SCC, which would be an auxiliary test for the pathological assessment of the ambiguous cases.

Human papillomavirus genotypes and P16INK4A expression in squamous penile carcinoma in Mexican patients.

BACKGROUND: Approximately 50% of cases of penile carcinoma (PeCa), a rare neoplasm worldwide, are associated with human papillomavirus (HPV). However, the detection of HPV-DNA is not sufficient to consider it the etiological factor in the development of this type of cancer. Currently, the overexpression of P16INK4A is used as a surrogate biomarker of HPV carcinogenesis. Information on PeCa in Mexico is scarce, particularly regarding cases related to HPV and genotype frequency. OBJECTIVE: To evaluate the presence of HPV, its genotypes, and the presence of multiple genotypes, and the expression of P16INK4A, as well as its clinical and histopathological parameters. METHODS: For HPV-DNA detection and P16INK4A expression, we used the INNO-LiPA® test and immunohistochemistry, respectively. RESULTS: Sixty cases of PeCa were evaluated, of which 75% were HPV-non-related histological variants. We found that 58.9% (33/56) of PeCa cases were HPV-DNA positive, while 30.9% of the cases evaluated (17/55) were positive for P16INK4A. HPV16 was the main genotype in 42.9% of the cases, followed by HPV52 in 7.1% and HPV18 in 5.4%. Within the HPV-positive cases, 27.3% had multiple genotypes. All HPV-positive patients under the age of 45 years were positive only for HPV16. CONCLUSIONS: HPV16 was the most commonly detected genotype in PeCa. HPV 31, 35 and 39 were infrequent; however, they were related to a single infection and P16INK4A overexpression; thus, they seem to be relevant in PeCa carcinogenesis. Our results suggest that P16INK4A overexpression could be useful for the classification of HPV-related PeCa. The role of multiple HPV genotypes in the development and prognosis of PeCa is still not completely understood. Thus, it is necessary to define criteria to establish reliable ways to classify HPV-related PeCa that could lead to optimal therapeutic approaches.

Tumor classification with MALDI-MSI data of tissue microarrays: A case study.

With mass spectrometry imaging (MSI) on tissue microarrays (TMAs) a large number of biomolecules can be studied for many patients at the same time, making it an attractive tool for biomarker discovery. Here we investigate whether lymph node metastasis can be predicted from MALDI-MSI data. Measurements are performed on TMAs and then filtered based on spectral intensity and the percentage of tumor cells, after which the resulting data for 122 patients is further preprocessed. We assume differences between patients with and without metastasis are expressed in a limited number of features. Two univariate feature selection methods are applied to reduce the dimensionality of the MALDI-MSI data. The selected features are then used in combination with three classifiers. The best classification scores are obtained with a decision tree classifier, which classifies about 72% of patients correctly. Almost all the predictive power comes from a single peak (m/z 718.4). The sensitivity of our classification approach, which can be generically used to search for biomarkers, is investigated using artificially modified data.

Clinical and molecular classification of vulvar squamous pre-cancers.

Vulvar intraepithelial neoplasia (VIN) is a precursor to vulvar squamous cell carcinoma and is defined histopathologically by the presence of atypia. VIN has been classified into two types: usual vulvar intraepithelial neoplasia (uVIN), which is also referred to as a vulvar high-grade squamous intra-epithelial lesion (HSIL), and differentiated VIN (dVIN). The former is associated with chronic infection by sub-types of the human papilloma virus (HPV), whereas dVIN is HPV-independent and frequently associated with lichen sclerosus. The distinction is important because dVIN has a greater risk of, and more rapid transit to, vulvar squamous cell carcinoma. Furthermore, dVIN-associated vulvar cancers have an increased risk of recurrence and higher mortality than those arising from HSIL. Molecular characterization of vulvar squamous cell carcinoma precursors using next-generation sequencing is a relatively novel, but rapidly advancing field. This review appraises recent studies that have investigated the risks of progression to vulvar malignancy associated with HSIL and dVIN, the prognosis of HPV-dependent and HPV-independent vulvar squamous cell carcinomas, and conducted next generation sequencing mutation analyses to elucidate the genomic profiles underlying VIN. These studies suggest that HSIL and dVIN are characterized by different underlying molecular alterations that may have important implications for treatment and follow-up of women diagnosed with vulvar squamous cell cancer.

Squamous Cell Carcinoma of the Nail Unit: A Clinical Histopathologic Study and a Proposal for Classification.

BACKGROUND: There is no consensus on the classification, grading, and the treatment of nail squamous cell carcinoma (NSCC). OBJECTIVE: The aim of the study was to propose a possible classification of NSCC. MATERIALS AND METHODS: Nail squamous cell carcinoma referred from January 2006 till December 2014 was included. On the basis of the clinical presentation, patients with NSCC were divided in 2 groups. Group A tumors presented as nodular or ulcerated masses of the nail bed, whereas Group B tumors presented as hyperkeratotic bands. In these 2 groups, differences in proportions (sex, histopathologic grading, and treatment performed) were evaluated with the chi-square test. RESULTS: Forty-one NSCCs were included. The groups of NSCC differed regarding: (1) the age of the patients, (2) histopathology, and (3) surgical approach. CONCLUSION: Nail squamous cell carcinomas may originate from 2 different epithelia, presenting a diverse clinical behavior. The correct identification and diagnosis of each subgroup of NSCC could be helpful in standardizing management of this tumor. Future studies considering human papillomavirus subtyping and including a major number of tumors should be performed to confirm or reject the authors' hypothesis. LIMITATIONS: This is a retrospective study, presenting the data and the experience of a single institute.

Histological classification of cutaneous squamous cell carcinomas with different severity.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer. Histology represents the gold standard to confirm the diagnosis of cSCC and is mandatory to determine important findings for tumour grading, such as tumour thickness, depth of invasion, degree of differentiation and histological subtype, perineural and vascular invasion, and assessing tumour margins. In daily clinical practice, the combination of clinical and histological features should be considered when grading the tumours and treating the patients, accordingly. This article aims to provide a structured overview of the most common histological findings of in situ and invasive cSCCs, namely those relevant to their severity, and should facilitate the understanding and evaluation of these results.

Cytomorphological criteria for separation of pulmonary adenocarcinomas from squamous cell carcinomas: A statistical learning approach.

BACKGROUND: Current therapy requires separation of non-small cell carcinomas into adenocarcinomas (AC) and squamous cell carcinomas (SCC). A meta-analysis has shown a pooled diagnostic sensitivity of 63% and specificity of 95% for the diagnosis of AC. While a number of cytomorphological features have been proposed for separation of AC from SCC, we are unaware of a statistically based analysis of cytomorphological features useful for separation of these two carcinomas. We performed logistic regression analysis of cytological features useful in classifying SCC and AC. DESIGN: Sixty-one Papanicolaou-stained fine needle aspiration specimens (29 AC/32 SCC) were reviewed by two board-certified cytopathologists for nine features (eccentric nucleoli, vesicular chromatin, prominent nucleoli, vacuolated cytoplasm, 3-dimensional cell balls, dark non-transparent chromatin, central nucleoli, single malignant cells and spindle-shaped cells). All cytological specimens had surgical biopsy results. Inter-rater agreement was assessed by Cohen's κ. Association between features and AC was determined using hierarchical logistic regression model where feature scores were nested within reviewers. A model to classify cases as SCC or AC was developed and verified by k-fold verification (k = 5). Classification performance was assessed using the area under the receiver operating characteristic curve. RESULTS: Observed rater agreement for scored features ranged from 49% to 82%. Kappa scores were clustered in three groups. Raters demonstrated good agreement for prominent nucleoli, vesicular chromatin and eccentric nuclei. Fair agreement was seen for 3-dimensional cell balls, dark non-transparent chromatin, and presence of spindle-shaped cells. Association of features with adenocarcinoma showed four statistically significant associations (P < 0.001) with adenocarcinoma. These features were prominent nucleoli, vesicular chromatin, eccentric nuclei and three-dimensional cell balls. Spindle-shaped cells and dark non-transparent chromatin were negatively associated with adenocarcinoma. CONCLUSIONS: Logistic regression analysis demonstrated six features helpful in separation of AC from SCC. Prominent nucleoli, vesicular chromatin, cell balls and eccentric nucleoli were positively associated with AC and demonstrated a P value of 0.001 or less. The presence of dark, non-transparent chromatin and spindle-shaped cells favoured the diagnosis of SCC.

The utility of TTF-1, napsin A, CK5 and p63 staining in the sub-classification of non-small cell carcinoma of the lung.

BACKGROUND: The potentially curative and/or palliative therapy for non-resectable lung cancer has evolved significantly over the past 2 decades. With the availability of targeted therapies, the need for precise sub-typing of non-small cell lung carcinoma (NCSLC) has become paramount. OBJECTIVES: As there are few data from South Africa, we aimed to determine utility of TTF-1, napsin A, p63 and CK5 immunostaining on fine needle aspiration (FNA) cell block and formalin-fixed paraffin-embedded tissue biopsy specimens in subtyping NSCLC as adenocarcinoma and squamous cell carcinomas. METHODS: All cases of NSCLC diagnosed during a 3-year period were retrospectively identified. All FNA biopsy and formalin-fixed paraffin-embedded cases that were stained with TTF-1, napsin A, CK5 and p63 were collected. A lung cancer registry was used to access and correlate clinical and radiological data. RESULTS: We included 271 cases with diagnoses of adenocarcinoma of the lung (n = 201), squamous cell carcinoma of the lung (n = 53), unspecified NSCLC (n = 8) and other carcinomas (n = 9). TTF-1 and napsin A had sensitivities of 99.0% and 91.9%, respectively, positive predictive values (PPVs) of 90.8% and 90.3%, respectively, and accuracies of 91.0% for adenocarcinoma of the lung. Napsin A had a higher specificity than TTF-1 (90.2% vs 62.8%). Both CK5 and P63 had high sensitivities (95.4% and 97.9%, respectively) and negative predictive values of 96.4% and 96.8%, respectively, for squamous cell carcinoma of the lung. CK5 had a higher specificity than p63 (84.4% and 61.2%, respectively), PPV (80.4% and 70.8%, respectively) and accuracy (88.8% and 79.2%, respectively) for squamous cell carcinoma. CONCLUSION: All four immunostaining methods had high sensitivities. TTF-1 and napsin A both had high PPV and diagnostic accuracy for adenocarcinoma of the lung, whereas CK5 had an equally high PPV and accuracy for squamous cell carcinoma of the lung. The specificity of napsin A for adenocarcinoma was higher than that of TTF-1. The specificity of CK5 for squamous cell carcinoma was higher than p63.

[Classification of cutaneous squamous cell carcinoma : How do I recognise my high-risk patient?] / Klassifikation des Plattenepithelkarzinoms der Haut : Wie erkenne ich meinen Hochrisikopatienten?

Cutaneous squamous cell carcinomas are the second most common malignant tumours of the skin. In most cases, they are primarily treatable by surgery. Various risk factors for local recurrence as well as metastasis and tumor-specific death have been described. Various classification systems are available for risk stratification. Tumour thickness is the strongest risk factor for the development of local recurrences, but also for metastasis and tumour-specific death. In addition, the immune status of patients, location and histological factors such as growth patterns and differentiation play an important role in the assessment of the individual risk. According to these parameters, patients should be included in a risk-adapted follow-up regimen. The risk of local recurrence and metastasis is highest in the first few years after excision, which is why follow-up care should be more intensive during this time.

Ocular surface squamous neoplasia: analysis based on the 8th American Joint Committee on Cancer classification.

PURPOSE: To evaluate outcomes of ocular surface squamous neoplasia (OSSN) based on American Joint Committee on Cancer (AJCC), 8th edition classification. METHODS: Retrospective, non-randomized interventional case series of 127 patients (136 eyes) with OSSN. RESULTS: On the basis of the AJCC (eighth edition), OSSN was classified as per T category as Tis (n = 14, 10%), T1 (n = 0), T2 (n = 4, 3%), T3 (n = 113, 83%), and T4 (n = 5, 4%). The following parameters increased with increasing T category: mean age at presentation at 37 years for Tis, 43 years for T2, 46 years for T3, and 55 years for T4 (p = 0.04); mean tumor basal diameter of 4 mm for Tis, not applicable (na) for T1, 6 mm for T2, 7 mm for T3, 20 mm for T4 (p = 0.001); extent of clock hours of corneal involvement (0, na, 0, 4, 8; p = 0.02), and conjunctival involvement (1, na, 2, 3, 9; p = 0.0005); involvement of adjacent structures including fornix (0%, na, 0, 9, 80%; p < 0.001), and caruncle (0%, na, 0, 3, 60%; p < 0.001) for Tis, T1, T2, T3, and T4, respectively. Overall, of the 136 eyes, 19 (14%) had tumor recurrence, and all tumor recurrences were seen in T3. Regional lymph node metastasis was noted in 4 (3%) patients. No systemic metastasis or death occurred in any patient during the mean follow-up period of 15 months (median, 11 months; range 6-55 months). CONCLUSION: Increasing T category based on AJCC 8th edition classification is associated with increasing severity of disease, tumor recurrence rate, and the rate of regional lymph node metastasis.

Genome analyses identify the genetic modification of lung cancer subtypes.

Lung cancer is a highly intricate and heterogeneous disease with genomic diversity in each subtype. Global analyses of gene expression and sequencing provided us new understanding of the genetic variation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), including adenocarcinoma (ADC), and squamous cell carcinoma (SCC). The genetic variations of lung cancer subtypes in genomic studies were integrated and further analyzed using bioinformatics methods. The lung cancer subtypes share some genetic variations such as the dysfunction of tumor suppressor gene TP53, and also harbor specific variations of their own such as MET in ADC, FGFR1 and FGFR3 in SCC and MYC in SCLC. The activated pathway in lung ADC and SCC mainly focuses on MAPK and PI3K with different key genes of each, respectively, and the activated pathway of SCLC mainly focuses on JAK-STAT pathway. The diagnosis of lung cancer subtypes based on these genetic variations such as SNP was also evaluated. These results provide further insights into the different pathogenesis of lung cancer subtypes.

A global view of regulatory networks in lung cancer: An approach to understand homogeneity and heterogeneity.

A number of new biotechnologies are used to identify potential biomarkers for the early detection of lung cancer, enabling a personalized therapy to be developed in response. The combinatorial cross-regulation of hundreds of biological function-specific transcription factors (TFs) is defined as the understanding of regulatory networks of molecules within the cell. Here we integrated global databases with 537 patients with lung adenocarcinoma (ADC), 140 with lung squamous carcinoma (SCC), 9 with lung large-cell carcinoma (LCC), 56 with small-cell lung cancer (SCLC), and 590 without cancer with the understanding of TF functions. The present review aims at the homogeneity or heterogeneity of gene expression profiles among subtypes of lung cancer. About 5, 136, 52, or 16 up-regulated or 19, 24, 122, or 97down-regulated type-special TF genes were identified in ADC, SCC, LCC or SCLC, respectively. DNA-binding and transcription regulator activity associated genes play a dominant role in the differentiation of subtypes in lung cancer. Subtype-specific TF gene regulatory networks with elements should be an alternative for diagnostic and therapeutic targets for early identification of lung cancer and can provide insightful clues to etiology and pathogenesis.