Prognostic implications of neuroendocrine differentiation and hormone production in patients with Stage I nonsmall cell lung carcinoma

Pelosi, Giuseppe; Pasini, Felice; Sonzogni, Angelica; Maffini, Fausto; Maisonneuve, Patrick; Iannucci, Antonio; Terzi, Alberto; Manzoni, Giovanni De; Bresaola, Enrica; Viale, Giuseppe

doi:10.1002/cncr.11376

Cited by 89 publications

(72 citation statements)

References 60 publications

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“…Predominantly mixed-type adenocarcinomas, 40 three acinar adenocarcinomas, one solid mucin producing adenocarcinoma and one bronchioloalveolar (BA)/lepidic mucinous adenocarcinoma/mucinous adenocarcinoma in situ were studied to validate the different patterns. Forty-two cases (93.3%) with acinar pattern (being the most prevalent), Thirteen cases (28.9%) showed lymph node metastasis as follows: acinar pattern was present in 13 cases (100%); solid and micropapillary patterns were present in 3 cases each (23%); and papillary pattern in 2 cases (15.4%).…”

Section: Resultsmentioning

confidence: 99%

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways

Sousa

Bastos

Silva

et al. 2015

Revista Portuguesa de Pneumologia (English Edition)

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Lung cancer is one of the most common cancers in the world with a high mortality rate. We analyzed 45 surgical samples of the adenocarcinoma, 13 with lymph node metastasis. APC, BCL2, chromogranin A, CK 5/6/18 (LP34), CK20, CK7, cyclin D1, EGFR, ERCC1, HER2, Ki67, LRP, MRP, P53, RB and TTF1 expressions were evaluated by immunohistochemistry (IHC).Higher Ki67, APC, ERCC1 expressions and lower TTF1 expression were identified in advanced stages (IIA and IIIA) of adenocarcinomas, which reflect a more aggressive, less differentiated, possibly a non-TRU adenocarcinoma.Acinar, micropapillary and BA/lepidic adenocarcinoma patterns were the most similar patterns and papillary was the most different pattern followed by solid pattern, according to expression of these markers. Different adenocarcinoma patterns are engaged with different molecular pathways for carcinogenesis, based on the differences of expression. Acinar, BA/lepidic and micropapillary showed higher TTF1 expression (type TRU), and papillary and solid patterns revealed less TTF1 expression, exhibiting a non-TRU/bronchial phenotype. Solid pattern revealed lower HER2 and higher EGFR and ERCC1 (this compared to papillary) expression; papillary higher HER2 and lower ERCC1 expressions; micropapillary higher RB expression; and acinar lower ERCC1 and higher EGFR expressions. Ciclin D1 seems to have more importance in acinar and BA/lepidic patterns than in micropapillary. ERCC1 protein expression in micropapillary, solid and BA/lepidic patterns may indicate DNA repair activation. Inhibition of apoptosis could be explained by BCL2 overexpression, present in all adenocarcinoma patterns. MRP-1 and LRP were overexpressed in all patterns, which may have implications for drug resistance.Further studies are needed to interpret these data regarding to therapy response in advanced staged bronchial-pulmonary carcinomas.

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Section: Resultsmentioning

confidence: 99%

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways

Sousa

Bastos

Silva

et al. 2015

Revista Portuguesa de Pneumologia (English Edition)

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“…13 Therefore, Merkel cell carcinoma seems to occupy an intermediate position between cutaneous squamous cell carcinoma and extracutaneous small cell carcinoma, so that Merkel cell carcinoma is much more aggressive than the former but less so than the latter. [2][3][4][5] Neuroendocrine differentiation is considered to carry a negative prognostic connotation in some carcinomas, 15 whereas other carcinoma types have yielded contradictory results 16,17 or shown just a trend toward an association between neuroendocrine differentiation and high tumor grade. 18 We found a statistically significant association of low (o10% of tumor cells) expression of synaptophysin with good outcome in Merkel cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles associated with aggressive behavior in Merkel cell carcinoma

et al. 2007

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Primary neuroendocrine carcinoma of the skin, or Merkel cell carcinoma, is the most aggressive cutaneous neoplasm. In spite of its similarities to small cell carcinomas from other locations, Merkel cell carcinoma shows many peculiarities probably related to its epidermal origin and the etiologic role of UV radiation. We have immunohistochemically investigated 43 markers on a tissue microarray in which 31 surgically resected Merkel cell carcinomas were represented. Of these, 15 patients remained free of disease after removal, whereas 16 developed metastases. Immunoreactivity was scored according to staining intensity and the percentage of positive cells. We found statistically significant correlations between metastatic tumor spread and overexpression of matrix metalloproteinase (MMP) 7, MMP10/2, tissue inhibitor of metalloproteinase 3, vascular endothelial growth factor (VEGF), P38, stromal NF-kappaB, and synaptophysin. Also detected were statistically significant correlations between the expression levels of MMP7 and VEGF, MMP7 and P21, MMP7 and P38, MMP10/2 and VEGF, P38 and synaptophysin, P38 and P53, and P21 and stromal NF-kappaB. These findings may be helpful in predicting the clinical course of Merkel cell carcinoma and are potentially useful for the development of targeted therapies.

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“…This report focuses on NE cells found in lung tumors and the NE-differentiation process. NSCLC that contain foci of NE cells constitute 10-35% of all NSCLC and have been proposed to be an intermediary step between NSCLC and SCLC (Graziano et al, 1994;Linnoila et al, 1994;Gosney et al, 1995;Pelosi et al, 2003). Thus, the NE differentiation of NSCLC represents an excellent model for understanding the regulatory aspects of NE differentiation in lung cancer and thus the identification of key regulatory proteins for therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

“…In more recent studies, that correlation now seems less well defined (Jiang et al, 1999;Graziano et al, 2001;Yesner, 2001;Gajra et al, 2002). Nevertheless, recent studies using more defined NSCLC specimens demonstrated that stage I adenocarcinomas with more than 5% NE tumor cells are clinically aggressive tumors, and hormone production identifies a more fully developed NE phenotype but is not relevant to prognosis (Pelosi et al, 2003). Therefore, it seems more likely that study of a subset of NE-like differentiated NSCLC, delineated using NE markers as part of a more global determination scheme, can still be useful.…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine-like differentiation of non-small cell lung carcinoma cells: regulation by cAMP and the interaction of mac25/IGFBP-rP1 and 25.1

et al. 2006

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The need to develop more effective therapies for lung cancer has led to investigations in understanding the molecular mechanisms of the differentiation process, in particular neuroendocrine (NE) differentiation. Recent studies have demonstrated that NE differentiation in nonsmall cell lung carcinoma (NSCLC) is not uncommon. Those NSCLCs with NE differentiation are considered a form of in transition NE carcinoma and show a more aggressive clinical course compared with NSCLC without NE differentiation. 25.1, a novel protein interacting with mac25/insulin-like growth factor-binding protein-related protein 1 (mac25/IGFBP-rP1), induced NE-like differentiation when collectively overexpressed in M12 prostate cancer cells. We have examined mac25/IGFBP-rP1 and 25.1 as potential molecular regulators in vitro of the NEdifferentiation process in lung cancer. In a panel of SCLC and NSCLC cell lines, mac25/IGFBP-rP1 and 25.1 were expressed at higher levels in SCLC. An increase and sustained activation of adenosine 3 0 ,5 0 -cyclic monophosphate (cAMP) levels induced NE-like differentiation in NSCLC cell lines, and a concomitant increase in the expression of mac25/IGFBP-rP1 and 25.1 was observed during the cAMP-regulated differentiation of NCI-H157 cells, suggesting the involvement of these proteins. Furthermore, the collective overexpression of mac25/ IGFBP-rP1 and 25.1 in NSCLC cells induced NE-like differentiation as early as 6 h postinfection. The present data suggest that mac25/IGFBP-rP1 and 25.1 may play a functional role in the NE differentiation of NSCLC cell lines and may provide a novel therapeutic target for treating lung cancers, in particular NSCLC with NE differentiation.

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Prognostic implications of neuroendocrine differentiation and hormone production in patients with Stage I nonsmall cell lung carcinoma

Cited by 89 publications

References 60 publications

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways

Expression profiles associated with aggressive behavior in Merkel cell carcinoma

Neuroendocrine-like differentiation of non-small cell lung carcinoma cells: regulation by cAMP and the interaction of mac25/IGFBP-rP1 and 25.1

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