Updated World Health Organization Classification Research Articles

Prognostic Effect of CDKN2A Homozygous Deletion and Beclin 1 in Isocitrate Dehydrogenase Mutant Glial Tumors

ABSTRACT Background: In the updated World Health Organization Classification of Central Nervous System Tumors, the presence of CDKN2A/2B homozygous deletion is now recognized as the indicative of Grade 4 in isocitrate dehydrogenase (IDH) mutant astrocytomas, and it is associated with a poor prognosis in Grade 4 astrocytomas. Conversely, Beclin 1, a crucial protein in autophagy initiation, exhibits a bidirectional effect on tumor progression and suppression. The objective of this study is to evaluate CDKN2A homozygous deletion in IDH mutant astrocytomas of varying grades, to compare it with microvascular proliferation (MVP) and palisading necrosis, and to analyze the relationship between these findings and Beclin 1 expression, subsequently comparing them with prognosis. Subjects and Methods: CDKN2A homozygous deletion and Beclin 1 expression were analyzed in 32 cases with IDH-mutant diffuse astrocytomas of Grades 2, 3, and 4. Results: CDKN2A homozygous deletion was detected in one of 10 patients with Grade 2 and in 8 of 17 patients with Grade 4. Beclin 1 was positively stained in 2 of Grade 2 astrocytomas, 4 of Grade 3 astrocytomas, and 9 of Grade 4 astrocytomas. While Beclin 1 expression was present in 5 of 9 cases with CDKN2A homozygous deletion, no expression was observed in four cases. Conclusion: In this study, the prognostic significance of CDKN2A homozygous deletion alone was found to be lower compared to the deletion in combination with MVP and/or necrosis. At the same time, Beclin 1 expression was determined to exert no prognostic significance alone, while it was found to exert a poor prognostic effect in combination with CDKN2A homozygous deletion.

An Illustrated Review of the Recent 2019 World Health Organization Classification of Neuroendocrine Neoplasms: A Radiologic and Pathologic Correlation.

Recent advances in molecular pathology and an improved understanding of the etiology of neuroendocrine neoplasms (NENs) have given rise to an updated World Health Organization classification. Since gastroenteropancreatic NENs (GEP-NENs) are the most common forms of NENs and their incidence has been increasing constantly, they will be the focus of our attention. Here, we review the findings at the foundation of the new classification system, discuss how it impacts imaging research and radiological practice, and illustrate typical and atypical imaging and pathological findings. Gastroenteropancreatic NENs have a highly variable clinical course, which existing classification schemes based on proliferation rate were unable to fully capture. While well- and poorly differentiated NENs both express neuroendocrine markers, they are fundamentally different diseases, which may show similar proliferation rates. Genetic alterations specific to well-differentiated neuroendocrine tumors graded 1 to 3 and poorly differentiated neuroendocrine cancers of small cell and large-cell subtype have been identified. The new tumor classification places new demands and creates opportunities for radiologists to continue providing the clinically most relevant report and on researchers to design projects, which continue to be clinically applicable.

Spinal Ependymomas: An Updated WHO Classification and a Narrative Review.

Ependymomas are neuroepithelial tumors that develop from ependymal cells found in the brain parenchyma and can spread to any part of the spinal cord. Three to six percent of all malignanciesaffecting the central nervous system (CNS) are ependymomas. Even the most talented surgeons are challenged by spinal cord ependymomas; as a result, research into this clinical phenomenon should continue. Since 1979, the World Health Organization (WHO) has published a classification and grading system for CNS malignancies to ensure consistent diagnostic standards worldwide. The WHO prepared an update on these tumors, paying particular attention to molecular techniques to categorize the therapeutic management of each patient with greater accuracy and clarity.We thoroughly reviewedthe literature on the epidemiology, etiology, diagnosis, and treatment of spinal ependymomas since there has not been a recent review of these tumors. This included modifications to the 2021 WHO Classification of Tumors of the Central Nervous System.

Proton MR spectroscopy shows improved performance to segregate high-grade astrocytoma subgroups when defined with the new 2021 World Health Organization classification of central nervous system tumors.

The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors prioritizes isocitrate dehydrogenase (IDH) mutation to define tumor types in diffuse gliomas, in contrast to the 2016 classification, which prioritized histological features. Our objective was to investigate the influence of this change in the performance of proton MR spectroscopy (1H-MRS) in segregating high-grade diffuse astrocytoma subgroups. Patients with CNS WHO grade 3 and 4 diffuse astrocytoma, known IDH mutation status, and available 1H-MRS were retrospectively retrieved and divided into 4 groups based on IDH mutation status and histological grade. Differences in 1H-MRS between groups were analyzed with the Kruskal-Wallis test. The points on the spectrum that showed the greatest differences were chosen to evaluate the performance of 1H-MRS in discriminating between grades 3 and 4 tumors (WHO 2016 defined), and between IDH-mutant and IDH-wildtype tumors (WHO 2021). ROC curves were constructed with these points, and AUC values were calculated and compared. The study included 223 patients with high-grade diffuse astrocytoma. Discrimination between IDH-mutant and IDH-wildtype tumors showed higher AUC values (highest AUC short TE, 0.943; long TE, 0.864) and more noticeable visual differences than the discrimination between grade 3 and 4 tumors (short TE, 0.885; long TE, 0.838). Our findings suggest that 1H-MRS is more applicable to classify high-grade astrocytomas defined with the 2021 criteria. Improved metabolomic robustness and more homogeneous groups yielded better tumor type discrimination by 1H-MRS with the new criteria. The 2021 World Health Organization classification of brain tumors empowers molecular criteria to improve tumor characterization. This derives in greater segregation of high-grade diffuse astrocytoma subgroups by MR spectroscopy and warrants further development of brain tumor classification tools with spectroscopy. • The new 2021 updated World Health Organization classification of central nervous system tumors maximizes the role of molecular diagnosis in the classification of brain tumors. • Proton MR spectroscopy performs better to segregate high-grade astrocytoma subgroups when defined with the new criteria. • The study provides additional evidence of improved metabolic characterization of brain tumor subgroups with the new criteria.

Novel insight into histological and molecular astrocytoma, IDH-mutant, Grade 4 by the updated WHO classification of central nervous system tumors.

The latest fifth edition of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors (WHO CNS 5 classification) released in 2021 defined astrocytoma, IDH-mutant, Grade 4. However, the understanding of this subtype is still limited. We conducted this study to describe the features of astrocytoma, IDH-mutant, Grade 4 and explored the similarities and differences between histological and molecular subtypes. Patients who underwent surgery from January 2011 to January 2022, classified as astrocytoma, IDH-mutant, Grade 4 were included in this study. Clinical, radiological, histopathological, molecular pathological, and survival data were collected for analysis. Altogether 33 patients with astrocytoma, IDH-mutant, Grade 4 were selected, including 20 with histological and 13 with molecular WHO Grade 4 astrocytoma. Tumor enhancement, intratumoral-necrosis like presentation, larger peritumoral edema, and more explicit tumor margins were frequently observed in histological WHO Grade 4 astrocytoma. Additionally, molecular WHO Grade 4 astrocytoma showed a tendency for relatively longer overall survival, while a statistical significance was not reached (47 vs. 25 months, p = 0.22). TP53, CDK6, and PIK3CA alteration was commonly observed, while PIK3R1 (p = 0.033), Notch1 (p = 0.027), and Mycn (p = 0.027) alterations may affect the overall survival of molecular WHO Grade 4 astrocytomas. Our study scrutinized IDH-mutant, Grade 4 astrocytoma. Therefore, further classification should be considered as the prognosis varied between histological and molecular WHO Grade 4 astrocytomas. Notably, therapies aiming at PIK3R1, Notch 1, and Mycn may be beneficial.

The Updated World Health Organization Classification Better Predicts Survival in Patients With Endocervical Adenocarcinoma (KROG 20-07)

The 2020 World Health Organization classification divided endocervical adenocarcinoma (ADC) into human papillomavirus-associated (HPVA) and human papillomavirus-independent (HPVI) ADCs. This multi-institutional study aimed to investigate the clinical features and prognosis of patients with endocervical ADC based on the updated World Health Organization classification. We retrospectively reviewed the 365 patients with endocervical ADC who underwent radical hysterectomy from 7 institutions. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs. Two hundred seventy-five (75.3%) and 90 (24.7%) patients had HPVA and HPVI ADC diagnoses, respectively. In all cases, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 58.2% and 71.3%, respectively. HPVI ADC showed higher rates of local recurrence (25.6% vs 10.9%) and distant metastasis (33.3% vs 17.5%) than HPVA ADC. Multivariate survival analysis revealed that HPVI ADC showed significantly worse DFS (hazard ratio [HR], 1.919; 95% confidence interval [CI], 1.324-2.781; P < .001), distant metastasis-free survival (HR, 2.100; 95% CI, 1.397-3.156; P < .001), and OS (HR, 2.481; 95% CI, 1.586-3.881; P < .001) than HPVA ADC. Patients with gastric- and serous-type HPVI ADC had significantly worse OS than those with other HPVI ADCs (P=.020). Similarly, invasive stratified mucin-producing-type HPVA ADC showed significantly worse OS than other HPVA ADCs (P < .001). We demonstrated that HPVI ADC exhibited inferior DFS and OS and higher rates of local and distant recurrence compared with HPVA ADC. Gastric- and serous-type HPVI ADCs and invasive stratified mucin-producing-type HPVA ADC showed worse OS than other types of HPVI and HPVA ADCs, respectively. Our observation of significant differences in prognoses according to the histologic types needs to be validated in larger cohorts of patients with endocervical ADC.

Clinical updates on gliomas and implications of the 5th edition of the WHO classification of central nervous system tumors.

The 5th edition of the World Health Organization (WHO) classification of central nervous system tumors incorporated specific molecular alterations into the categorization of gliomas. The major revision of the classification scheme effectuates significant changes in the diagnosis and management of glioma. This study aimed to depict the clinical, molecular, and prognostic characteristics of glioma and its subtypes according to the current WHO classification. Patients who underwent surgery for glioma at Peking Union Medical College Hospital during 11 years were re-examined for tumor genetic alterations using next-generation sequencing, polymerase chain reaction-based assay, and fluorescence in situ hybridization methods and enrolled in the analysis. The enrolled 452 gliomas were reclassified into adult-type diffuse glioma (ntotal=373; astrocytoma, n=78; oligodendroglioma, n=104; glioblastoma, n=191), pediatric-type diffuse glioma (ntotal=23; low-grade, n=8; high-grade, n=15), circumscribed astrocytic glioma (n=20), and glioneuronal and neuronal tumor (n=36). The composition, definition, and incidence of adult- and pediatric-type gliomas changed significantly between the 4th and the 5th editions of the classification. The clinical, radiological, molecular, and survival characteristics of each subtype of glioma were identified. Alterations in CDK4/6, CIC, FGFR2/3/4, FUBP1, KIT, MET, NF1, PEG3, RB1, and NTRK2 were additional factors correlated with the survival of different subtypes of gliomas. The updated WHO classification based on histology and molecular alterations has updated our understanding of the clinical, radiological, molecular, survival, and prognostic characteristics of varied subtypes of gliomas and provided accurate guidance for diagnosis and potential prognosis for patients.

Genomic and epigenomic re-categorization of congenital glioblastoma and desmoplastic infantile ganglioglioma.

The recently updated World Health Organization classification of central nervous system (CNS)tumors, 5th edition, (CNS5) reclassifies pediatric tumors according to their distinct molecular drivers, recognizing anew entity-infant-type hemispheric glioma (IHG). Defined by its unique epigenetic signature, and/or genomicfusions in ALK, ROS1, NTRK, or MET gene, IHG subsumes many cases previously classified as congenitalglioblastoma (cGBM). Histologic features of IHG are still poorly defined with known overlap with a clinic radiologicallysimilar entity-desmoplastic infantile ganglioglioma/astrocytoma (DIG). We revisited our cohort of cGBMs and DIGs, now reclassifying them according to CNS5 and comparedthe clinical, radiologic, molecular and histologic features between the two. 3/6 cases of cGBM that underwent targeted NGS fusion mutation panel were positive for ALK fusions(involving MAP4, MZT2Bex2, and EML4 genes as fusion partners), and 1/6 showed GOPC:ROS1 fusion.Interestingly, GOPC:ROS1 fusion was also shared by 1/5 cases of histologically defined DIG. DNA methylationprofiling using the Heidelberg classifier (v12.3) recategorized 2/5 DIG cases as IHG (including the case with ROS1alteration). In conclusion, histology alone is insufficient to distinguish IHG from DIG, necessitating epigenomic andgenomic testing for the diagnosis of early-life gliomas.

Mature T-cell and NK-cell lymphomas: updates on molecular genetic features.

Mature T-cell and NK-cell lymphomas are a heterogeneous group of rare and typically aggressive neoplasms. Diagnosis and subclassification have historically relied primarily on the integration of clinical, histologic, and immunophenotypic features, which often overlap. The widespread application of a variety of genomic techniques in recent years has provided extensive insight into the pathobiology of these diseases, allowing for more precise diagnostic classification, improved prognostication, and development of novel therapies. In this review, we summarize the genomic features of the most common types of mature T-cell and NK-cell lymphomas with a particular focus on the contribution of genomics to biologic insight, classification, risk stratification, and select therapies in the context of the recently published International Consensus and updated World Health Organization classification systems.

Single-Cell Sequencing Analysis Identified ASTN2 as a Migration Biomarker in Adult Glioblastoma.

Glioblastoma is the most common and aggressive primary central nervous system malignant tumors. With the development of targeted sequencing and proteomic profiling technology, some new tumor types have been established and a series of novel molecular markers have also been identified. The 2021 updated World Health Organization classification of central nervous system tumors first mentioned the classification of adult glioma and pediatric glioma based on the molecular diagnosis. Thus, we used single-cell RNA sequencing analysis to explore the diversity and similarities in the occurrence and development of adult and pediatric types. ASTN2, which primarily encodes astrotactin, has been reported to be dysregulated in various neurodevelopmental disorders. Although some studies have demonstrated that ASTN2 plays an important role in glial-guided neuronal migration, there are no studies about its impact on glioblastoma cell migration. Subsequent single-cell RNA sequencing revealed ASTN2 to be a hub gene of a cell cluster which had a poor effect on clinical prognosis. Eventually, a western blot assay and a wound-healing assay first confirmed that ASTN2 expression in glioblastoma cell lines is higher than that in normal human astrocytes and affects the migration ability of glioblastoma cells, making it a potential therapeutic target.

Endocervical Adenocarcinoma: Comprehensive Histological Review and Re-classification of 123 Consecutive Cases According to the Updated World Health Organization Classification of Female Genital Tumors.

The updated 2020 World Health Organization (WHO) classification divides endocervical adenocarcinomas (EACs) into human papillomavirus-associated (HPVA) and -independent (HPVI) tumors. The purpose of this study was to review our EAC cases and re-classify them according to the updated WHO classification. We reviewed the hematoxylin and eosin-stained slides of 123 EACs and reclassified them according to the updated WHO classification. Eighty-one (65.9%) and 42 (34.1%) patients had HPVA and HPVI EACs, respectively. The usual (60/81; 74.1%) and gastric (31/42; 73.8%) types were the most common HPVA and HPVI EACs, respectively. Signet-ring cell (1/123; 0.8%), invasive stratified mucin-producing (10/123; 8.1%), clear-cell (4/123; 3.3%), mesonephric (3/123; 2.4%), and serous (1/123; 0.8%) types were uncommon. Unusual morphologies were seen, including microcystic, elongated, and fragmented patterns of stromal invasion, micropapillary growth patterns, and gastric-type adenocarcinoma in situ. We successfully reclassified all the examined cases based on morphology alone. The numbers and relative proportions of EAC histotypes were variable. We found some uncommon histotypes, as well as unusual but clinically important histological features.

Open versus minimally invasive radical hysterectomy for early cervical cancer: A two-center retrospective cohort study with pathologic review of usual-type adenocarcinoma and adenosquamous carcinoma

ObjectiveTo compare survival outcomes of minimally invasive surgery (MIS) and open surgery for radical hysterectomy (RH) in early cervical cancer patients with histologic subtypes of usual-type adenocarcinoma and adenosquamous carcinoma. MethodsFrom two centers' cervical cancer cohorts, patients with 2009 FIGO stage IB1–IB2 who underwent RH between 2007 and 2020 were retrospectively identified. Patients with usual-type adenocarcinoma and adenosquamous carcinoma were included in the analysis after pathologic review according to the updated World Health Organization Classification of Tumors. Clinicopathologic characteristics and survival outcomes were compared in terms of open surgery or MIS. ResultsThis study included 161 patients. No significant differences were noted in overall survival (OS; P = 0.241) and disease-free survival (DFS; P = 0.156) between patients with usual-type adenocarcinoma (n = 136) and those with adenosquamous carcinoma (n = 25). MIS RH group (n = 99) had a significantly smaller tumor size (P < 0.001), lesser pathologic parametrial invasion (P = 0.001), and lesser lymph node metastasis (P < 0.001) than open RH group (n = 62). MIS and open RH groups showed similar OS (P = 0.201) and 3-year DFS rate (87.9% vs. 75.1%; P = 0.184). In multivariate analysis, worse DFS was not associated with MIS (P = 0.589) but was associated with pathologic parametrial invasion (adjusted HR, 3.41; 95% CI, 1.25–9.29; P = 0.016). Consistent results were observed among patients with usual-type adenocarcinoma; MIS was not associated with worse DFS. ConclusionsComparable survival outcomes were found for MIS and open RH in early-stage cervical usual-type adenocarcinoma and adenosquamous carcinoma. Although MIS RH was not a poor prognostic factor, pathologic parametrial invasion was significantly associated with worse DFS in cervical usual-type adenocarcinoma and adenosquamous carcinoma.

Nonsquamous Lesions of the Vulvar Skin and Subcutaneous Tissue: A Review (Part 2).

The aim of this second article was to complete part 1 review of nonsquamous lesions of the vulvar skin and subcutaneous tissue (Journal of Lower Genital Tract Disease, 2021), clinically and pathologically, based on the fifth edition of the World Health Organization tumor classification. A database search of PubMed and Google Scholar was performed between 1970 and 2021, using the search terms "vulva," "lower genital tract," and "non-squamous lesions." The search was limited to "human gynecological pathology." Full article texts were reviewed, and reference lists were screened for additional articles. We excluded abstracts and articles written in the non-English language. An initial list of 400 articles was identified. Thirty-seven articles discussed clinicopathological features of nonsquamous lesions of the vulvar skin and subcutaneous tissue. Clinicopathological features of nonsquamous lesions of the vulvar skin and subcutaneous tissue as categorized by the updated World Health Organization classification are presented.

Predicting prognosis according to the updated WHO classification in patients with endocervical adenocarcinoma treated with surgery and radiotherapy.

The recently updated World Health Organization classification divides endocervical adenocarcinomas (ADCs) into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) ADCs. This study aimed to investigate the differences in the clinical features and treatment outcomes between patients with HPVA and HPVI. We retrospectively reviewed the electronic medical records and pathology slides of 123 patients with endocervical ADC who underwent radical hysterectomy and adjuvant radiation therapy. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs. Eighty-one (65.9%) and 42 (34.1%) patients were diagnosed with HPVA and HPVI ADCs, respectively. HPVI ADC showed more frequent positive vaginal resection margin (VRM) and peritoneal seeding than HPVA ADC. After a median follow-up of 58.1 months, local recurrence and distant metastasis were more frequently observed in HPVI ADC than in HPVA ADC. Both local recurrence-free survival (77.3% vs. 91.8%) and distant metastasis-free survival (50.1% vs. 73.7%) rates of HPVI ADC were lower than those of HPVA ADC. Disease-free survival was not significantly different between HPVI and HPVA ADCs. We demonstrated that HPVI ADC exhibited higher rates of VRM involvement and peritoneal seeding than those of HPVA ADC, resulting in higher rates of local recurrence and distant metastasis. Further studies with larger populations are warranted to explore optimal treatment strategies based on the histological subtypes of endocervical ADC.

Up-to-date Knowledge on the Pathological Diagnosis of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) has heterogeneous molecular and pathological features and biological behavior. Large-scale genetic studies of HCC were accumulated, and a pathological-molecular classification of HCC was proposed. Approximately 35% of HCCs can be classified into distinct histopathological subtypes according to their molecular characteristics. Among recently identified subtypes, macrotrabecular massive HCC, neutrophil-rich HCC, vessels encapsulating tumor clusters HCC, and progenitor phenotype HCC (HCC with CK19 expression) are associated with a poor prognosis, whereas the lymphocyte-rich HCC subtype is related to a better prognosis. This review provides up-to-date knowledge on the pathological diagnosis of HCC according to the updated World Health Organization Classification of Digestive System Tumors 5th ed.

The updated WHO classification of digestive system tumours-gastric adenocarcinoma and dysplasia.

The fifth edition of the World Health Organization (WHO) classification of digestive system tumours was published in 2019. The classification of invasive carcinoma is basically the same as in the fourth edition, but the description of each histological type has been updated, and some rare subtypes such as micropapillary carcinoma, gastric adenocarcinoma of the fundic gland type and undifferentiated carcinoma have been added and explained. Although this classification did not provide specific numerical criteria for the diagnosis of signet-ring cell carcinoma in poorly cohesive carcinoma, an additional study defined signet-ring cell carcinoma as having more than 90% signet-ring cells. The molecular classification of gastric cancer (Epstein-Barr virus-positive type, microsatellite instability type, genomically stable type, chromosomally unstable type) was additionally introduced. Many pages in the present classification have been devoted to precancerous lesions, and this article focuses on foveolar-type adenoma/dysplasia.

Updated WHO classification of tumors of the breast

In the fifth edition of the World Health Organization (WHO) classification of tumors of the breast, the histological features of the lesions continue to form the basis of the classification; however, molecular pathology nowadays provides approaches for improved diagnostics and prediction of prognosis and treatment response, which have been incorporated into the update of the classification. The most important changes are presented, which include changes in the histological classification of invasive carcinomas, the subtyping of lobular carcinoma in situ (LCIS) and the dignity criteria of phyllodes tumors.

Nonsquamous Lesions of the Vulvar Skin and Subcutaneous Tissue: A Review (Part 1).

This article aimed to review "nonsquamous lesions of the vulvar skin and subcutaneous tissue" clinically and pathologically, based on the fifth edition of the World Health Organization tumor classification. A database search of PubMed and Google Scholar was performed between 1970 and 2021, using the search terms "vulva," "lower genital tract," and "nonsquamous lesions." The search was limited to "humans," "gynecopathology," and "dermatopathology." Full article texts were reviewed. Reference lists were screened for additional articles. We excluded articles written in the non-English language and abstracts. A list of 600 articles was identified. Another screening identified 68 articles for clinicopathological features of nonsquamous lesions of the vulvar skin and subcutaneous tissue. In the first part of this review, we cover 5 major groups of nonsquamous lesions of the vulvar skin and subcutaneous tissue including (1) glandular tumors and cysts, (2) adenocarcinomas of other types, (3) germ cell tumors of the vulva, (4) neuroendocrine neoplasia, and (5) hematolymphoid hyperplasia and neoplasia. The rest of the major topics including mesenchymal tumors of the lower genital tract, melanocytic lesions, and metastasis will be discussed in the second part of this review. Clinicopathological features of nonsquamous lesions of the vulvar skin and subcutaneous tissue as categorized by the updated World Health Organization classification are presented.

Progress in the pathological arena of gynecological cancers.

This review covers the significant new developments in the pathological classification of gynecological tumors. Many of these were included in the updated World Health Organization Classification of Female Genital Tract Tumours, published in 2020. Topics include the compelling evidence that a large majority of extrauterine high‐grade serous carcinomas arise from the fallopian tube; the Cancer Genome Atlas (TCGA) Classification of endometrial carcinomas; the discovery that most so‐called synchronous endometrial and ovarian endometrioid carcinomas represent metastasis from the endometrium to the ovary; and the division of cervical, vaginal, and vulval carcinomas into clinically meaningful HPV‐associated and HPV‐independent types. Newly described tumor types are covered, including endometrial and ovarian mesonephric‐like adenocarcinoma, uterine sarcoma types associated with specific molecular abnormalities, and gastric (gastrointestinal)‐type adenocarcinomas of the endometrium and vagina. Important molecular events in ovarian sex cord–stromal tumors are also discussed.

Relationship between molecular changes in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in lung adenocarcinoma*

Abstract Objective This study aimed to analyze the relationship between the mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) and their impact on the prognosis and treatment of lung adenocarcinoma. Methods A total of 158 cases of lung adenocarcinoma reported between January 2007 and January 2014 were retrospectively analyzed. These tumors were resected using radical pneumonectomy and underwent pathology-based diagnosis at our institution (Inner Mongolia People’s Hospital, Hohhot, China). The tissue sections were evaluated using the updated World Health Organization classification of lung adenocarcinomas (2015 version), with each histological component recorded in 5% increments. The histological subtypes were classified, and any surviving cases were followed up. The reverse transcription-polymerase chain reaction (RT-PCR) and direct DNA sequencing were used to evaluate mutations in exons 18, 19, 20, and 21 in the EGFR gene, and the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) fusions were detected using sequencing. Results Our cohort included 25 patients with pre-invasive adenocarcinoma, 13 patients with lepidic, 66 patients with acinar, 13 patients with papillary, and 25 patients with solid infiltrative adenocarcinoma with the remaining cases presenting with a variety of pathological subtypes. The prognosis of each histological subtype was different with the 5-year disease-free survival and 5-year overall survival (OS) of pre-invasion adenocarcinoma at 100%; the 5-year OS of lepidic, acinar, and papillary adenocarcinoma patients was only 84.6%, 72.7%, and 76.9%, respectively. The 5-year OS of solid and mucinous adenocarcinomas were 32.0% and 36.4%, respectively. EGFR mutation was detected in 69 cases with a mutation rate of 43.7% and majority of these mutations were found in exons 19 (50.6%) and 21 (37.9%), with women and non-smokers shown to experience a higher mutation rate (P &lt; 0.05). However, histological subtype analysis showed that EGFR mutations were primarily found in adenocarcinomas. Most of these mutations were found in lepidic (53.8%) or acinar adenocarcinomas (50.0%), whereas these mutations were rare in both solid (28.0%) and mucinous adenocarcinoma (27.2%). The fusion mutation rate in the EML4-ALK gene was 5.69%, and was most common in young, nonsmoking patients (P &lt; 0.05). Conclusion The prognosis of patients in each lung adenocarcinoma subtype is different, and these outcomes are likely related to mutations in the EGFR and EML4-ALK genes. EGFR mutation rates are higher in lepidic and acinar adenocarcinomas, whereas EML4-ALK gene fusion mutations are more common in solid and mucinous adenocarcinoma. EGFR mutations are more common in female and non-smoking patients, whereas EML4-ALK fusions are more common in young, non-smoking patients.