Associations Between Mutations and Histologic Patterns of Mucin in Lung Adenocarcinoma
Kyuichi KadotaYi‐Chen YehSandra P. D’AngeloAndré L. MoreiraDeborah KukCamelia S. SimaGregory J. RielyMaria E. ArcilaMark G. KrisValerie W. RuschPrasad S. AdusumilliWilliam D. Travis
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Multiple reports indicate that epidermal growth factor receptor (EGFR) mutations are associated with lepidic-pattern lung adenocarcinoma and that KRAS mutations are associated with invasive mucinous adenocarcinoma. We sought to investigate the association between EGFR and KRAS mutations and specific morphologic characteristics, such as predominant histologic subtype and mucinous features. Clinical data for 864 patients with resected lung adenocarcinoma that underwent molecular testing for EGFR and KRAS mutations were collected. Histologic subtyping was performed according to the IASLC/ATS/ERS lung adenocarcinoma classification, with attention given to signet-ring cell feature and extracellular mucin. EGFR mutations were detected using a polymerase chain reaction-based sizing assay, KRAS mutations were detected using Sanger sequencing, and ALK expression was detected using immunohistochemistry. Invasive mucinous adenocarcinoma was associated with KRAS mutation (P<0.001). Among invasive mucinous adenocarcinomas with KRAS mutation, a pure mucinous pattern was more common than a mixed mucinous/nonmucinous pattern (P=0.002). Invasive mucinous adenocarcinoma was associated with KRAS transition mutations (G→A) but not transversion mutations (G→T or G→C) compared with nonmucinous tumors (P=0.009). The lepidic-predominant group was associated with EGFR mutation compared with nonlepidic-predominant tumors (P=0.011). Extracellular mucin was associated with KRAS mutation (P<0.001), whereas signet-ring cell feature was not associated with EGFR or KRAS mutation (P=0.517). ALK expression was associated with signet-ring cell feature (P=0.001) but not with extracellular mucin (P=0.089). Our study shows that histologic patterns of mucin in lung adenocarcinoma-including invasive mucinous adenocarcinoma and extracellular mucin-are associated with KRAS mutation.Keywords:
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Abstract Context.—Signet-ring cell carcinoma (SRCC) is a poorly differentiated mucin-producing adenocarcinoma that may arise from many different organs, but all SRCCs share identical morphology. It is not possible to differentiate sites of origin for metastatic SRCC based on morphology alone. Mucins are high-molecular-weight glycoproteins differentially expressed in glandular epithelia and in adenocarcinomas. Objective.—To identify mucin profiles of primary and metastatic SRCCs using immunohistochemistry to determine whether mucin staining could help distinguish sites of origin. Design.—Forty-seven SRCCs, including 38 primary (21 stomach, 11 colorectum, and 6 breast) and 9 metastases from these primary sites were retrieved from archival files. Consecutive tissue sections were immunostained with monoclonal antibodies against MUC1, MUC2, MUC4, MUC5AC (MUC5), and MUC6 on separate slides. Cytoplasmic staining was scored based on proportion of positive tumor cells as follows: 0+ (<5%), 1+ (5%–25%), 2+ (26%–50%), and 3+ (>50%). Mucin profiles were recorded as MUC+, MUCv, and MUC− for consistent, variable, and negative expression, respectively. Results.—The mucin profiles for gastric, colorectum, and breast SRCCs are MUC1·2·4·5·6v, MUC2·4+/MUC5v/ MUC1·6−, and MUC1+/MUC2·5·6v/MUC4−, respectively. Mucin profiles of metastatic cases shared profiles with their respective primaries. Conclusions.—Signet-ring cell carcinomas of the stomach, colorectum, and breast have distinct mucin expression patterns that are maintained in metastases. Mucin profiling may be useful to identify the origin of a metastatic SRCC of unknown primary.
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Since the introduction of immunohistochemisty, histochemical staining is used progressively less frequent. However, this stains have its usage. Routine histochemical staining of mucins stain extracelular mucins, and cell intracellular vacuoles. Mucin in tumors can have the same histochemical characteristics like the mucin produced by normal cell of the same origin, but in many cases it differs. We selected 60 gastric carcinomas classified by 13-th Japanese classification and divided at: 8 mucinous, 10 signet ring cell carcinomas, 20 well and moderately differentiated tubular carcinomas (10 of each), and 22 poorly differentiated solid and non-solid carcinomas. In all cases analyzed mucin was PAS positive, and in most of the cases alcian-blue positive. Most of mucin positive tumor cells had sialomucins granules. In both well and poorly differentiated carcinomas neutral mucins can be the only mucin produced which indicate gastric tumor cell's phenotype. Tumor cell of signet ring cell carcinomas produce sialomucins, and less frequently sulfo and neutral mucins.
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Epidermal growth factor receptor (EGFR) mutations are a potential predictor of the effectiveness of EGFR inhibitors for the treatment of lung cancer. Although EGFR mutations were reported to occur with high frequency in nonsmoking Japanese adenocarcinoma patients, the exact nature has not been fully elucidated. We examined EGFR gene mutations within exons 18-21 and their correlations to clinico-pathological factors and other genetic alterations in tumour specimens from 154 patients who underwent resection for lung cancer at Kyoto University Hospital. Epidermal growth factor receptor mutations were observed in 60 tumours (39.0%), all of which were adenocarcinoma. Among the patients with adenocarcinoma (n=108), EGFR mutations were more frequently observed in nonsmokers than former smokers or current smokers (83.0, 50.0, 15.2%, respectively), in women than men (76.3 vs 34.0%), in tumours with bronchio-alveolar component than those without bronchio-alveolar component (78.9 vs 42.9%), and in well or moderately differentiated tumours than poorly differentiated tumours (72.0, 64.4, 34.2%). No tumours with EGFR mutations had any K-ras codon 12 mutations, which were well-known smoking-related gene mutations. In conclusion, adenocarcinomas with EGFR mutation had a distinctive clinico-pathological feature unrelated to smoking. Epidermal growth factor receptor mutations may play a key role in the development of smoking-independent adenocarcinoma.
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A 70-year-old male case of mucinous cystic adenocarcinoma of the lung with signet-ring cells was reported. Patient was operated with diagnosis suspicious lung cancer by the specimen from TBLB. But, intraoperative rapid pathological-diagnosis was confused us for no cellular component, finally we performed right upper lobectomy and R1 LN dissection. Postoperative histological examination showed that the tumor was entirely filled with mucin and there are a few tumor cells with the signet-ring shape in its marginal area. So, this tumor was diagnosed as mucinous cystic adenocarcinoma of the lung with signet ring cells. This type of the lung adenocarcinoma was rare case, but we need to have much attentions because of the clinical differences from the other type of adenocarcinoma.
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<div>Abstract<p>Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (<i>EGFR</i>) and Kirsten ras (<i>KRAS</i>) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic <i>KRAS</i>, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands. (Cancer Res 2005; 65(24): 11478-85)</p></div>
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Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands.
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<div>Abstract<p>Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (<i>EGFR</i>) and Kirsten ras (<i>KRAS</i>) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic <i>KRAS</i>, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands. (Cancer Res 2005; 65(24): 11478-85)</p></div>
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