Well-differentiated liposarcoma/atypical lipomatous tumor (WDLS/ALT) and dedifferentiated liposarcoma (DDLS) have characteristic supernumerary ring and giant marker chromosomes involving the ...chromosomal region 12q13-15 which contains MDM2 (12q15), CDK4 (12q14.1), HMGA2 (12q14.3), YEATS4 (12q15), CPM (12q15), and FRS2 (12q15). Detecting MDM2 amplification by fluorescence in situ hybridization (FISH) is considered to be the gold standard for the diagnosis of WDLS/ALT and DDLS. In this study, formalin fixed paraffin embedded clinical specimens (16 liposarcomas and 19 benign lipomatous tumors) were used to detect MDM2 amplification and other chromosomal alterations in WDLS/ALT and DDLS by single nucleotide polymorphism-based chromosome microarray (CMA). All 16 liposarcomas showed MDM2 amplification with a MDM2/cep12 ratio from 2.4 to 8.4 by CMA. Ten (62.5%) of these cases had CDK4/cep12 ratio ≥2.0. All the cases without CDK4 amplification were from the thigh. The MDM2/cep12 ratio of all the benign lipomatous tumors (19/19) was within the normal limits. Twenty-one of the 35 benign lipomatous tumors and liposarcomas were also tested for MDM2 amplification by FISH. All the FISH results were consistent with the CMA results (100%). Along with MDM2 amplification, all 16 liposarcomas (100%) also showed amplification of YEATS4, CPM and FRS2. Only 11 of 16 (69%) cases showed HMGA2 amplification. In conclusion, this study demonstrated that CMA on routine formalin fixed paraffin embedded tissue is a sensitive and specific clinical test for detection of MDM2 gene amplification. Moreover, CMA allows simultaneous detection of genomic changes of interest including CDK4 and others, which provides enriched information for diagnosing lipomatous tumors.
Objective
Targeted therapy is an important part of the treatment of lung adenocarcinoma. Tests for EGFR mutation, ALK, ROS1, RET and NTRK gene fusions are needed to make a treatment decision. These ...gene fusions are traditionally detected by fluorescence in situ hybridisation (FISH) or immunohistochemistry. In this study, we investigated whether gene fusions in pulmonary adenocarcinoma could be accurately detected by RNA next‐generation sequencing (RNA‐NGS) and whether cytology cell blocks could be used effectively for this test.
Methods
Archived cytological specimens of lung adenocarcinoma submitted for RNA sequencing between 2019 and 2022 at Fox Chase Cancer Center were retrospectively retrieved. Hybrid capture‐based targeted RNA next generation sequencing was used, which covers 507 fusion genes, including ALK, ROS1, RET and NTRKs, irrespective of their partner genes. DNA NGS, FISH and chromosomal microarray analysis were used to confirm the results of the RNA‐NGS.
Results
A total of 129 lung adenocarcinoma cytology specimens were submitted for molecular testing. Eight of 129 (6.2%) cases were excluded from RNA sequencing as their cell blocks contained inadequate numbers of tumour cells. One case (0.8%) failed to yield adequate RNA. The overall success rate was 93% (120/129). Ten of 120 (8.3%) cytology cases were positive for gene fusions, including 7 ALK, 2 ROS1 fusion genes, and 1 RET fusion gene. Twenty‐two cell block cases were also tested for ALK fusion genes using FISH. However, 11 of 22 (50%) failed the testing due to inadequate material.
Conclusions
Cytology cell blocks can be used as the main source of material for molecular testing for lung cancer. Detection of gene fusions by RNA‐based NGS on cell blocks is convenient and reliable in daily practice.
Gene fusions of EML4‐ALK, RDX‐ROS1 and KIF5B‐RET.
Mediastinal adenofibroma: a case report Durra, Heba; Khurana, Jasvir; Flieder, Douglas B
Histopathology,
September 2014, Volume:
65, Issue:
3
Journal Article
Summary Purpose This is a retrospective analysis of the impact of moderate dysplasia at the resection margin for early stage cancer of the oral tongue. Materials and methods Patients with T1-2N0 oral ...tongue cancer treated with surgery alone at Fox Chase Cancer Center (FCCC) from 1990 to 2010 were reviewed. Tumor and margin characteristics were abstracted from the pathology report. Overall survival (OS), disease-free survival (DFS) and local control (LC) were calculated using the Kaplan Meier method. Predictors of LC, OS and DFS were analyzed. Results 126 Patients met the inclusion criteria. Dysplasia was present at the final margin in 36% of the cases (severe: 9%, moderate: 15%, mild: 12%). Median follow-up was 52 months. 3 and 5-year actuarial LC for the entire cohort was 77% and 73%, respectively. Actuarial 5-year LC and DFS were significantly worse for patients with moderate or severe dysplasia at the margin vs. none or mild dysplasia at the margin (49% vs 82%, p = 0.005 and 49% vs 80%, p = 0.008, respectively); 3-year comparisons were not significant. When analyzed separately, the detrimental local effect of moderate dysplasia at the margin persisted ( p = 0.02) and the effect of severe dysplasia at the margin was approaching significance ( p = 0.1). Mild dysplasia at the margin did not significantly impair LC or DFS. Multivariate analysis demonstrated worse LC (HR: 2.99, p = 0.006) and DFS (HR: 2.84, p = 0.008) associated with severe or moderate dysplasia at the margin. Conclusions Both severe and moderate dysplasia at the margin appear to be correlated with inferior LC and DFS. Additional therapy may be justified, despite added morbidity.
Lung cancer is the leading cause of cancer mortality in women worldwide. Although the rise and growing epidemic status of lung cancer are overwhelmingly attributed to tobacco use, its rank in ...nonsmokers as the seventh most common cause of cancer worldwide suggests that other factors contribute to this disease. The majority of lung cancers among nonsmokers occur in women. Aside from geographic, cultural, and genetic differences, hormonal and possibly infectious factors also may play etiologic roles. This review aims to discuss the epidemiology of lung cancer in women, as well as the incidence of second primaries, and presents current opinions on the myriad of causes.
To review recent advances in pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC).
A pathology/CT review panel of pathologists and radiologists met ...during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The purpose was to determine if existing data was sufficient to propose modification of criteria for adenocarcinoma and BAC as newly published in the 2004 WHO Classification of Lung Tumors, and to address the pathologic/radiologic concept of diffuse/multicentric BAC.
Solitary small, peripheral BACs have an excellent prognosis. Most lung adenocarcinomas with a BAC pattern are not pure BAC, but rather adenocarcinoma, mixed subtype with invasive patterns. This applies to tumors presenting with a diffuse/multinodular as well as solitary nodule pattern. The percent of BAC versus invasive components in lung adenocarcinomas appears to be prognostically important. However, a consensus definition of "minimally invasive" BAC with a favorable prognosis could not be achieved. While recognition of a BAC component is possible, the diagnosis of BAC with exclusion of invasive adenocarcinoma cannot be made by small biopsy or cytology specimens.
There is a need to work toward a mutual understanding and consensus between pathologists, clinicians, and researchers with the use of the term BAC versus adenocarcinoma. Future studies should make some attempt to quantitate these components and/or other features such as size of scar, size of invasive component, or pattern of invasion. Hopefully, this work will allow definition of a category of adenocarcinoma, mixed subtype with predominant BAC/minimal invasion and a favorable prognosis.
The surgical pathologist's role in the diagnosis of adverse pulmonary and pleural drug effect requires an appreciation of the clinico-radiologic scenario and particular knowledge of morphologic ...patterns of lung injury. Bronchoscopic biopsies may be helpful in some cases of DAD, eosinophilic pneumonia, or OP. Extrapolating patterns of lung involvement from small biopsies and cytologic preparations often is difficult and surgical lung biopsy is required. Although lung biopsies are not pathognomonic for drug toxicity and correlation with clinical, laboratory, and radiologic data is required, they can be a powerful tool in the evaluation of suspected drug-induced pulmonary disease by helping to exclude underlying disease or infection and documenting the pattern of lung injury. The latter information is helpful in making the diagnosis of drug toxicity as well as guiding the optimal management of the patient.
Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international ...multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies.
An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach.
The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized.
This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.
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