Transformation from EGFR/PTEN co‐mutated lung adenocarcinoma to small cell carcinoma in lymph node metastasis

There is minimal evidence of EGFR‐mutated lung adenocarcinoma transforming to small cell lung carcinoma (SCLC) without the administration of EGFR‐tyrosine kinase inhibitor (TKI). Here, we present a case of EGFR/PTEN co‐mutated lung adenocarcinoma with lymph node metastases, which comprised adenocarcinoma admixed with SCLC. EGFR L858R and PTEN R130Q mutations were shared between the primary tumor and lymph node metastasis. Additionally, EGFR I744M mutation was shared between the adenocarcinoma and SCLC components in the lymph node metastasis, confirming spontaneous transformation from adenocarcinoma to SCLC. Furthermore, TP53 and RB1 mutations were detected only in the SCLC components of the lymph node metastasis. Immunohistochemically, complete absence of Rb expression in SCLC was observed, suggesting the loss of function of RB1. Our case clearly shows that EGFR/PTEN co‐mutated lung adenocarcinoma transformed to SCLC in the lymph node without TKI‐mediated evolutionary selection pressures.     

Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma

The appropriate selection of patients is a major challenge in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Prospective trials in adenocarcinoma demonstrated that the mucinous subtype presents a poorer outcome under EGFR-TKI treatment than the non-mucinous subtype. Our aim was to determine the molecular characteristics associated with resistance to EGFR-TKIs in mucinous and non-mucinous adenocarcinoma. Eighty adenocarcinoma samples, including 34 tumours from patients treated with gefitinib in a phase II clinical trial (IFCT0401), were classified as mucinous (n = 32) or non-mucinous (n = 48) adenocarcinoma. We demonstrated that four biological markers were differentially expressed between the two subtypes: mucinous tumours that overexpressed IGF1R (p < 0.0001) and amphiregulin (p = 0.004) with a tendency for more frequent KRAS mutations, in contrast to non-mucinous tumours that overexpressed EGFR (p < 0.0001) and TTF-1 (p < 0.0001) with more frequent EGFR mutations (p = 0.037). Higher IGF1R (p = 0.02) and lower TTF-1 (p = 0.02) expression was associated with disease progression under gefitinib treatment. We observed in vitro cross-talk between EGFR and IGF1R signalling pathways in gefitinib-resistant H358 mucinous cells. Anti-amphiregulin siRNAs and anti-IGF1R treatments sensitized the H358 cells to gefitinib-induced apoptosis with additive effects, suggesting that these treatments could overcome the resistance of mucinous tumours to EGFR-TKIs, including those with KRAS mutation. Our results highlighted that mucinous and non-mucinous adenocarcinoma subtypes are different entities with different therapeutic responses to EGFR-TKIs. These data will foster the development of therapeutic strategies for treating adenocarcinoma with mucinous component.     

Fine‐needle aspiration cytology of non‐small cell lung carcinoma: A paradigm shift

Lung carcinoma is one of the commonest causes of cancer related death. Fine‐needle aspiration cytology (FNAC) is a well‐established technique in the diagnosis of various malignant tumors. FNAC is now an important technique in classifying lung carcinomas and also detecting salient mutational changes in lung carcinomas. The judicious use of the various immunological markers such as TTF‐1, p40, CK 5/6, CK 7 and Napsin may help in sub‐classification of non‐small cell lung carcinomas (NSCLC). The mutational changes in epidermal growth factor receptor (EGFR) and ALK genes are needed in targeted therapy of adenocarcinoma of lung. With the help of immunocytochemistry, polymerase chain receptor, fluorescent in situ hybridization and next generation sequencing, one can detect various mutational changes in NSCLC. In this review article, we have discussed the role of cytology and other ancillary techniques to classify lung carcinomas. The important mutational changes in lung carcinoma for targeted therapy have also been discussed in detail.     

Mucin-producing adenocarcinoma of the lung, with special reference to goblet cell type adenocarcinoma: Immunohistochemical observation and Ki-ras gene mutation

To clarify its biological nature, 10 samples of goblet cell-type adenocarcinoma of the lung were collected and compared with 10 other pulmonary much-producing adene carcinomas with respect to Immunohistochemical features and the presence of Ki- ras gene mutation in codons 12 and 13. Goblet cell-type adenocarcinomas lacked lmmunoreactlvlty for surfactant apoprotein and S-100 protein-positive Langerhans cells, which was in marked contrast to other mucin-producing adenocarcinomas. In addition, the mucin gene products, MUC-1 and MUC-2 glycoproteins were immunohistochemically stained. The msuh showed that MUC-1 giycoprotein is frequently expressed by mucin-producing adenocarcinomas except the goblet cell-type. Ki- ras gene mutation was detected in 12 of 20 (60%) mucin-producing adenocarcinomas. These mutations were exclusively found in codon 12 and G to A transitions were the most frequent type of alteration in the KI- ras gene. In goblet cell-type adenocarcinomas, the frequency of KI- ras gene mutation was 80% consisting of G to A transitions and G to T transversions in six and two tumors, respectively. Therefore, goblet cell-type adenocarcinomas differed from other mucin-producing adeno-carcinomas in terms of immunohistochemical and molecular biological features, suggesting that goblet cell-type adenocarclnomas are distinctly different from other subtypes of adenocarcinomas.     

Value of P63 and CK5/6 in distinguishing squamous cell carcinoma from adenocarcinoma in lung fine‐needle aspiration specimens

The current FDA‐approved standard of care for nonsmall cell lung cancer is Carboplastin/Taxol/Avastin based upon an impressive survival benefit; however, patients with squamous carcinoma (SQCC) cannot receive Avastin because of a 30% mortality rate due to fatal hemoptysis. In this study we evaluated the role of cytomorphology and immunohistochemistry in differentiating SQCC from adenocarcinoma (ADC) in lung FNA specimens. The case cohort included 53 FNA cases of nonsmall cell lung carcinoma with surgical pathology follow‐up. All FNA specimens were reviewed independently by a panel of cytopathologists to differentiate between SQCC and ADC. The cell block material was available in 23 cases (11 ADC and 12 SQCC) to perform immunohistochemical stains for TTF‐1, CK7, CK20, P63, and CK5/6. On surgical resection, 35/53 (66%) cases were diagnosed as ADC and 18/53 (34%) as SQCC. The number of cases classified correctly on the basis of cytomorphology was 66% for ADC and 53% for SQCC (combined accuracy 60%). By immunohistochemical staining, 14/23 (61%) cases expressed TTF‐1. Nine cases were TTF‐1 negative; eight of the TTF‐1 negative cases (89%) were SQCC. Twenty‐three cases expressed CK7 (87%); one ADC case (4%) showed focal CK20 positivity. Both P63 and CK5/6 expression was seen in 9/12 (75%) SQCC cases; none of the ADC cases showed this dual expression. Cytomorphology alone may not be able to stratify all cases of nonsmall cell lung carcinoma into ADC and SQCC in FNA specimens. The immune‐panel of TTF‐1, CK7, CK20, P63, and CK5/6 is useful in differentiating SQCC from ADC. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Napsin A (TA02) is a useful alternative to thyroid transcription factor-1 (TTF-1) for the identification of pulmonary adenocarcinoma cells in pleural effusions

The purpose of this study was to test napsin A as a diagnostic marker of metastatic lung adenocarcinoma in pleural effusions, and to compare its performance with TTF-1. Napsin A and TTF-1 reactivities were determined immunohistochemically on formalin-fixed paraffin embedded cell blocks from 50 pleural effusion (5 mesotheliomas, 10 mesothelial proliferations, 12 pulmonary, and 23 nonpulmonary metastases). The results were evaluated separately, and correlated to the final diagnoses. Concordant results were obtained in 48/50 cases. TTF-1 and Napsin A were positive in 8/12 and 10/12 pulmonary adenocarcinomas, respectively. Both markers were negative in 42 cases, including two lung carcinomas. Napsin reactivity was found in more than 75% of the tumor cells in 9/10 positive cases, whereas TTF-1 reactivity was seen in more than 75% of the tumor cells in 2/8 positive cases only (P < 0.05). This makes napsin A an alternative to TTF-1 in cytological diagnosis of effusions in which tumor cells may be scanty.