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Archives of Pathology & Laboratory... Jul 2009Lung cancer is a common disease frequently seen by the surgical pathologist. Although secondary to improvements in screening and radiologic techniques and aggressive... (Review)
Review
CONTEXT
Lung cancer is a common disease frequently seen by the surgical pathologist. Although secondary to improvements in screening and radiologic techniques and aggressive resection of small pulmonary nodules, the diagnosis of preneoplastic lesions is increasing in frequency and importance. Consequently, a greater understanding of their role in the development of lung carcinoma is needed for optimal patient care. Two lesions often encountered as small pulmonary nodules are bronchioloalveolar carcinoma and adenocarcinoma, which can be challenging to distinguish. Recently, updates to the TNM classification of non-small cell lung carcinoma have been reported that directly impact prognosis and treatment algorithms. Identification of new molecular targets in pleural mesothelioma and in preneoplastic lesions may lead to improved therapeutic strategies.
OBJECTIVE
To present recent advances in our understanding of neoplastic lung diseases and mesothelioma and to describe how these advances relate to the current practice of pulmonary pathology.
DATA SOURCES
Published literature from PubMed (National Library of Medicine) and primary material from the authors' institution.
CONCLUSIONS
It is important for the surgical pathologist to understand current diagnostic classifications of non-small cell lung cancer and to be aware of the range of preneoplastic lesions, as well as the features useful for distinguishing bronchioloalveolar carcinoma from adenocarcinoma in small pulmonary nodules. Although pleural mesothelioma has distinct features, it can also overlap histologically with adenocarcinoma, and immunohistochemistry can greatly aid in accurate diagnosis. New therapies targeting molecular markers in both non-small cell lung cancer and mesothelioma rely on accurate histopathologic diagnosis of these entities.
Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Carcinoma, Non-Small-Cell Lung; Diagnosis, Differential; Humans; Lung Neoplasms; Mesothelioma; Prognosis
PubMed: 19642737
DOI: 10.5858/133.7.1106 -
British Journal of Cancer Mar 2001Transgenic mouse models were established to study tumorigenesis of bronchiolo-alveolar adenocarcinomas derived from alveolar type II pneumocytes (AT-II cells)....
Transgenic mouse models were established to study tumorigenesis of bronchiolo-alveolar adenocarcinomas derived from alveolar type II pneumocytes (AT-II cells). Transgenic lines expressing the murine oncogene c- myc under the control of the lung-specific surfactant protein C promoter developed multifocal bronchiolo-alveolar hyperplasias, adenomas and carcinomas respectively, whereas transgenic lines expressing a secretable form of the epidermal growth factor (IgEGF), a structural and functional homologue of transforming growth factor alpha (TGF alpha), developed hyperplasias of the alveolar epithelium. Since the oncogenes c- myc and TGF alpha are frequently overexpressed in human lung bronchiolo-alveolar adenocarcinomas, these mouse lines are useful as models for human lung bronchiolo-alveolar adenocarcinomas. The average life expectancies of hemizygous and homozygous c- myc transgenics were 14.25 months and 9.2 months, respectively, suggesting that a dosage effect of c- myc caused an accelerated bronchiolo-alveolar adenocarcinoma formation. First analyses of double transgenics, hemizygous for both c- myc and IgEGF, show that these mice develop bronchiolo-alveolar adenocarcinomas at the average age of 9 months, indicating that these oncogenes cooperate during the lung cancer formation. Our results demonstrate that c- myc and EGF are directly involved and cooperate with one another during formation of bronchiolo-alveolar adenocarcinomas in the lung.
Topics: Adenocarcinoma; Animals; Bronchial Neoplasms; Cloning, Molecular; Epidermal Growth Factor; Gene Expression; Genes, myc; Lung Neoplasms; Mice; Mice, Transgenic; Phenotype; Pulmonary Alveoli
PubMed: 11259097
DOI: 10.1054/bjoc.2000.1676 -
Journal of Toxicologic Pathology Jul 2022A 104-week-old male CD (SD) rat exhibited enlargement of the left testis. Microscopically, this mass was demarcated from the testis by fibrous connective tissue and...
A 104-week-old male CD (SD) rat exhibited enlargement of the left testis. Microscopically, this mass was demarcated from the testis by fibrous connective tissue and characterized by cystic dilatation with single-layered columnar cells and papillary proliferation connected to the solid growth area without clear boundaries. In the solid growth area, cells were dissected into irregular alveolar nests by scant fibrous tissue with small blood vessels. The nuclei of proliferating cells were variable in size and round- to oval-shaped, and their cytoplasm was pale or eosinophilic and sometimes contained vacuoles or eosinophilic granules. Immunohistochemically, the tumor cells were positive for vimentin and cytokeratin (CK) 7. Since CK7 was exclusively positive in the rete testis epithelium of the naïve rat, it was valuable to diagnose this tumor as rete testis-originated. Based on these results and the lack of apparent pleomorphism, mitotic figures, and metastasis, the present case was diagnosed as rete testis adenoma.
PubMed: 35832902
DOI: 10.1293/tox.2022-0018 -
Cancer Imaging : the Official... Oct 2009This article describes the aetiology, epidemiology and clinical significance of incidental non-solid pulmonary nodules. Non-solid nodules are more likely malignant. If... (Review)
Review
This article describes the aetiology, epidemiology and clinical significance of incidental non-solid pulmonary nodules. Non-solid nodules are more likely malignant. If malignant, they are mostly due to atypical adenomatous hyperplasia and bronchioloalveolar carcinoma. As these may be negative on positron emission tomography and slow growing, the diagnostic algorithms that are used for solid nodules have to be modified for non-solid nodules.
Topics: Adenocarcinoma, Bronchiolo-Alveolar; Adenoma; Adult; Aged; Algorithms; Follow-Up Studies; Humans; Hyperplasia; Incidental Findings; Lung Neoplasms; Mass Screening; Middle Aged; Positron-Emission Tomography; Precancerous Conditions; Solitary Pulmonary Nodule; Tomography, X-Ray Computed
PubMed: 19965304
DOI: 10.1102/1470-7330.2009.9046 -
Case Reports in Medicine 2012The alveolar adenoma of the lung is a rare benign tumor characterized by a proliferation of both the alveolar epithelial cells and the mesenchymal septal cells....
The alveolar adenoma of the lung is a rare benign tumor characterized by a proliferation of both the alveolar epithelial cells and the mesenchymal septal cells. Immunohistochemically, the epithelial cells stain for cytokeratin (CK) AE1AE3, CK7, thyroid transcription factor 1 (TTF1), and surfactant apoprotein confirming the derivation by the type 2 pneumocytes. The stromal cells are negative for these markers but they show focally smooth muscle and muscle-specific actin positivity. We describe two cases that showed immunohistochemically a CD34 positivity of the mesenchymal septal cells. This aspect has been previously described in a two cases report, but not emphasized by the authors as a distinctive feature of the lesion. We consider this CD34 positivity as a marker of immaturity or stemness of the lesional septal spindle cells, that could be responsible of the different phenotypic and morphological profile of the interstitial cells, that could be, therefore, considered neoplastic and not reactive.
PubMed: 23118769
DOI: 10.1155/2012/913517 -
PloS One 2011Mesothelioma is a highly malignant tumor that is primarily caused by occupational or environmental exposure to asbestos fibers. Despite worldwide restrictions on...
BACKGROUND
Mesothelioma is a highly malignant tumor that is primarily caused by occupational or environmental exposure to asbestos fibers. Despite worldwide restrictions on asbestos usage, further cases are expected as diagnosis is typically 20-40 years after exposure. Once diagnosed there is a very poor prognosis with a median survival rate of 9 months. Considering this the development of early pre clinical diagnostic markers may help improve clinical outcomes.
METHODOLOGY
Microarray expression arrays on mesothelium and other tissues dissected from mice were used to identify candidate mesothelial lineage markers. Candidates were further tested by qRTPCR and in-situ hybridization across a mouse tissue panel. Two candidate biomarkers with the potential for secretion, uroplakin 3B (UPK3B), and leucine rich repeat neuronal 4 (LRRN4) and one commercialized mesothelioma marker, mesothelin (MSLN) were then chosen for validation across a panel of normal human primary cells, 16 established mesothelioma cell lines, 10 lung cancer lines, and a further set of 8 unrelated cancer cell lines.
CONCLUSIONS
Within the primary cell panel, LRRN4 was only detected in primary mesothelial cells, but MSLN and UPK3B were also detected in other cell types. MSLN was detected in bronchial epithelial cells and alveolar epithelial cells and UPK3B was detected in retinal pigment epithelial cells and urothelial cells. Testing the cell line panel, MSLN was detected in 15 of the 16 mesothelioma cells lines, whereas LRRN4 was only detected in 8 and UPK3B in 6. Interestingly MSLN levels appear to be upregulated in the mesothelioma lines compared to the primary mesothelial cells, while LRRN4 and UPK3B, are either lost or down-regulated. Despite the higher fraction of mesothelioma lines positive for MSLN, it was also detected at high levels in 2 lung cancer lines and 3 other unrelated cancer lines derived from papillotubular adenocarcinoma, signet ring carcinoma and transitional cell carcinoma.
Topics: Animals; Antibodies, Neoplasm; Biomarkers; Cell Lineage; Cells, Cultured; Epithelial Cells; Epithelium; Gene Expression Regulation; Humans; Immunohistochemistry; In Situ Hybridization; Lung; Male; Membrane Proteins; Mesothelin; Mesothelioma; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Oligonucleotide Array Sequence Analysis; Organ Specificity; Reverse Transcriptase Polymerase Chain Reaction; Uroplakin III
PubMed: 21984916
DOI: 10.1371/journal.pone.0025391 -
Breast Cancer Research : BCR Oct 2015The diversity of human breast cancer subtypes has led to the hypothesis that breast cancer is actually a number of different diseases arising from cells at various...
INTRODUCTION
The diversity of human breast cancer subtypes has led to the hypothesis that breast cancer is actually a number of different diseases arising from cells at various stages of differentiation. The elusive nature of the cell(s) of origin thus hampers approaches to eradicate the disease.
METHODS
Clonal cell lines were isolated from primary transgenic polyomavirus middle T (PyVmT) luminal tumors. Mammary cancer stem cell (MaCSC) properties were examined by immunofluorescence, flow cytometry, differentiation assays and in vivo tumorigenesis.
RESULTS
Clonal cell lines isolated from primary PyVmT mouse mammary luminal tumors can differentiate into luminal, myoepithelial, alveolar and adipocyte lineages. Upon orthotopic injection, progeny of a single cell follow a pattern of progression from ductal carcinoma in situ, to adenoma, adenocarcinoma and epithelial metastasis that recapitulates the transgenic model. Tumors can evolve in vivo from hormone receptor-positive to hormone receptor-negative Her2-positive, or triple negative CD44hi basal-like and claudin-low tumors. Contrary to the current paradigm, we have defined a model in which multiple tumor subtypes can originate from a single multipotent cancer stem cell that undergoes genetic and/or epigenetic evolution during tumor progression. As in human tumors, the more aggressive tumor subtypes express nuclear p53. Tumor cell lines can also be derived from these more advanced tumor subtypes.
CONCLUSIONS
Since the majority of human tumors are of the luminal subtype, understanding the cell of origin of these tumors and how they relate to other tumor subtypes will impact cancer therapy. Analysis of clonal cell lines derived from different tumor subtypes suggests a developmental hierarchy of MaCSCs, which may provide insights into the progression of human breast cancer.
Topics: Adipocytes; Animals; Carcinogenesis; Cell Differentiation; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice, Inbred C57BL; Mice, Transgenic; Multipotent Stem Cells; Neoplastic Stem Cells; Transcriptome; Tumor Suppressor Protein p53
PubMed: 26467658
DOI: 10.1186/s13058-015-0615-y -
American Journal of Physiology. Lung... Sep 2013Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI), but the mechanisms leading to epithelial damage are not...
Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI), but the mechanisms leading to epithelial damage are not completely understood. Cell death by necrosis and apoptosis occurs in alveolar epithelial cells in the lungs of patients with ALI. Fas activation induces apoptosis of alveolar epithelial cells, but its role in the formation of lung edema is unclear. The main goal of this study was to determine whether activation of the Fas/Fas ligand pathway in the lungs could alter the function of the lung epithelium, and the mechanisms involved. The results show that Fas activation alters the alveolar barrier integrity and impairs the ability of the lung alveolar epithelium to reabsorb fluid from the air spaces. This result was dependent on the presence of a normal Fas receptor and was not affected by inflammation induced by Fas activation. Alteration of the fluid transport properties of the alveolar epithelium was partially restored by β-adrenergic stimulation. Fas activation also caused apoptosis of alveolar endothelial cells, but this effect was less pronounced than the effect on the alveolar epithelium. Thus, activation of the Fas pathway impairs alveolar epithelial function in mouse lungs by mechanisms involving caspase-dependent apoptosis, suggesting that targeting apoptotic pathways could reduce the formation of lung edema in ALI.
Topics: Acute Lung Injury; Adenoma; Adrenergic beta-Agonists; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Cell Membrane Permeability; Cytokines; Fas Ligand Protein; Humans; Inflammation; Isoproterenol; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Pulmonary Alveoli; Pulmonary Edema; Tumor Cells, Cultured; fas Receptor
PubMed: 23812636
DOI: 10.1152/ajplung.00271.2012 -
National Toxicology Program Technical... Sep 2010Androstenedione is an androgen steroid that is normally synthesized within men and women and may be metabolized to a more potent androgen or estrogen hormone. It was... (Review)
Review
UNLABELLED
Androstenedione is an androgen steroid that is normally synthesized within men and women and may be metabolized to a more potent androgen or estrogen hormone. It was nominated to the National Toxicology Program for study due to concern for adverse health effects associated with its chronic use as a dietary supplement by athletes (prior to the banning of its over the counter sales). In order to evaluate its subchronic and chronic toxicity, male and female F344/N rats and B6C3F1 mice were administered androstenedione (98% pure) by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, rat bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: groups of five male and five female rats were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 12 days. All rats survived to the end of the study, and the mean body weights of dosed groups were similar to those of the vehicle control groups. The development of cytoplasmic vacuoles within centrilobular hepatocytes in male rats was the only treatment-related effect observed. 2-WEEK STUDY IN MICE: groups of five male and five female mice were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 12 days. One vehicle control female, one 20 mg/kg female, and one 50 mg/kg female died early due to gavage accidents. There were no significant chemical-related histopathological or mean body weight changes. 3-MONTH STUDY IN RATS: groups of 10 male and 10 female core study rats were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 14 weeks; additional groups of 10 male and 10 female clinical pathology study rats received the same doses for 23 days. All rats survived to the end of the study. The mean body weights of the 20 mg/kg female group was significantly greater than those of the vehicle control group and there was significant increased weight gain in the 1, 20, and 50 mg/kg female groups. Female thymus weights were significantly increased in the 20 and 50 mg/kg groups, which may be related to the increase in mean body weight. The numbers of sperm per mg cauda epididymis in the 10, 20, and 50 mg/kg male groups and the total number of sperm per cauda epididymis in 50 mg/kg males were significantly less than those of the vehicle controls. No treatment-related histological lesions were observed in males or females. 3-MONTH STUDY IN MICE: groups of 10 male and 10 female mice were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 14 weeks. Except for one 10 mg/kg female that died early due to a dosing accident, all mice survived to the end of the study. The mean body weights of dosed groups were similar to those of the vehicle control groups. The number of spermatids per mg testis and the total number of spermatids per testis in 20 mg/kg males were significantly greater than those of the vehicle controls. Sperm motility in 50 mg/kg males was significantly lower than that in the vehicle controls. The incidences of x-zone atrophy of the adrenal cortex, an androgen-sensitive endpoint, were significantly increased in females administered 5 mg/kg or greater. There were also significant decreases in the incidences of x-zone cytoplasmic vacuolization in 20 and 50 mg/kg females. The incidences of bone marrow hyperplasia were significantly increased in 5 and 50 mg/kg males. 2-YEAR STUDY IN RATS: groups of 50 male and 50 female rats were administered 0, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for at least 104 weeks. Survival of 10 mg/kg males was significantly greater than that of the vehicle controls. The mean body weights of 20 and 50 mg/kg females were greater than those of the vehicle controls after weeks 17 and 9, respectively. The incidences of mononuclear cell leukemia were significantly increased in 20 and 50 mg/kg females and significantly decreased in 20 and 50 mg/kg males. Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in 20 mg/kg males. The incidence of testicular interstitial cell adenoma (including bilateral) was significantly decreased in 50 mg/kg males. In females, the incidences of mammary gland fibroadenoma were significantly decreased in the 20 and 50 mg/kg groups, the incidences of mammary gland hyperplasia were significantly decreased in all dosed groups, and the incidences of mammary gland cyst were significantly decreased in the 10 and 50 mg/kg groups. In the liver of males, the incidences of basophilic focus in all dosed groups, the incidence of clear cell focus in the 20 mg/kg group, and the incidence of eosinophilic focus in the 50 mg/kg group were significantly increased. The incidences of pancreatic islet hyperplasia and atrophy of the exocrine pancreas were significantly increased in 50 mg/kg females. 2-YEAR STUDY IN MICE: groups of 50 male and 50 female mice were administered 0, 2 (females only), 10, 20 (males only), or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for at least 104 weeks. Survival of dosed groups was similar to that of the vehicle control groups. Mean body weights of 10 and 50 mg/kg females were generally less than those of the vehicle controls after weeks 81 and 17, respectively. The incidences of hepatocellular adenoma in males and females were significantly increased in the 50 mg/kg groups. In females, the incidences of hepatocellular carcinoma were significantly increased in all dosed groups. Incidences of hepatocellular adenoma or carcinoma (combined) in males and females were significantly increased in the 50 mg/kg groups. Incidences of hepatoblastoma were marginally increased in dosed males. Incidences of multiple hepatocellular adenomas and carcinomas were significantly increased in 10 and 50 mg/kg males, and there was an increased incidence of multiple hepatocellular adenomas in 50 mg/kg females. The incidence of eosinophilic focus was significantly increased in 50 mg/kg males, and the incidences of mixed cell focus and cytoplasmic vacuolization were significantly increased in 50 mg/kg females. There was a marginally increased incidence of pancreatic islet adenoma in 50 mg/kg males and in 10 and 50 mg/kg females, with an earlier day of first incidence in males. The incidences of clitoral gland hyperplasia and clitoral gland duct dilatation were significantly increased in 10 and 50 mg/kg females. The incidence of glomerular metaplasia of the kidney was significantly increased in 50 mg/kg females, and the incidences of cytoplasmic alteration of the submandibular salivary gland were significantly increased in all dosed female groups. The increased incidences of cytoplasmic alteration of the submandibular salivary gland and glomerular metaplasia of the kidney in female mice indicated a masculinizing effect from androstenedione treatment. In 50 mg/kg females, the incidence of malignant lymphoma was significantly decreased.
GENETIC TOXICOLOGY
androstenedione was not mutagenic in either of two independent bacterial mutation assays conducted with and without exogenous metabolic activation. No significant increases in the frequencies of micronucleated polychromatic erythrocytes, indicators of chromosomal damage, were observed in bone marrow of male rats administered androstenedione by gavage once daily for 3 consecutive days. Results of a peripheral blood erythrocyte micronucleus test in mice, in which androstenedione was administered by gavage for 3 months, were negative in males but judged to be equivocal in females due to a small increase (twofold over background) in micronucleated normochromatic erythrocytes observed at the highest dose administered (50 mg/kg).
CONCLUSIONS
under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenic activity of androstenedione in male F344/N rats based on increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of androstenedione in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of androstenedione in male B6C3F1 mice based on increased incidences of multiple hepatocellular adenoma and hepatocellular carcinoma and increased incidence of hepatoblastoma. There was clear evidence of carcinogenic activity of androstenedione in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular carcinoma. Increased incidences of pancreatic islet adenoma in male and female mice were also considered chemical related. Androstenedione administration caused increased incidences in nonneoplastic lesions of the liver in male and female rats and mice; pancreatic islets and exocrine pancreas of female rats; and clitoral gland, kidney, and submandibular salivary gland of female mice. Decreases in the incidences of testicular interstitial cell adenoma in male rats, mammary gland fibroadenoma, cysts, and hyperplasia in female rats, and malignant lymphoma in female mice were considered related to androstenedione administration. Synonyms: Andro; androst-4-ene-3,17-dione; 4-androstene-3,17-dione; delta-4-androstene-3,17-dione; delta-4-androstenedione; 3,17-dioxoandrost-4-ene; 17-ketotestosterone; SKF 2170 Trade names: Androtex, Fecundin.
Topics: Androstenedione; Animal Feed; Animals; Biomarkers; Body Weight; Carcinogenicity Tests; Chemical and Drug Induced Liver Injury; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Estrous Cycle; Female; Genitalia; Intubation, Gastrointestinal; Male; Mice; Mice, Inbred Strains; Micronucleus Tests; Mutagens; Organ Size; Rats; Rats, Inbred F344
PubMed: 21037592
DOI: No ID Found -
Radiologia 2022
Topics: Humans; Radiography; Lung Neoplasms; Radiology; Adenoma
PubMed: 36402545
DOI: 10.1016/j.rxeng.2022.10.004