TTF1

Gene Summary

Gene:TTF1; transcription termination factor, RNA polymerase I
Aliases: TTF-1, TTF-I
Location:9q34.13
Summary:This gene encodes a transcription termination factor that is localized to the nucleolus and plays a critical role in ribosomal gene transcription. The encoded protein mediates the termination of RNA polymerase I transcription by binding to Sal box terminator elements downstream of pre-rRNA coding regions. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. This gene shares the symbol/alias 'TFF1' with another gene, NK2 homeobox 1, also known as thyroid transcription factor 1, which plays a role in the regulation of thyroid-specific gene expression. [provided by RefSeq, Apr 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:transcription termination factor 1
HPRD
Source:NCBIAccessed: 07 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 07 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 07 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TTF1 (cancer-related)

Zenali MJ, Weissferdt A, Solis LM, et al.
An update on clinicopathological, immunohistochemical, and molecular profiles of colloid carcinoma of the lung.
Hum Pathol. 2015; 46(6):836-42 [PubMed] Related Publications
Colloid carcinoma is a rare subtype of lung adenocarcinoma characterized by abundant pools of extracellular mucin and scant malignant epithelium. Because of the rarity of these tumors, many of the reported clinicopathological and immunohistochemical characteristics are contradictory. Moreover, the molecular alterations that underlie these tumors are unknown. We present the clinicopathological, immunohistochemical, and molecular features of 13 cases of colloid carcinoma of the lung. The patients were 9 women and 4 men between the ages of 48 and 86 years. Surgical resection and staging were performed in all patients. Seven patients were in stage T1N0M0, 3 in T2N0M0, 2 in T2N1M0, and 1 in T2N0M1. The tumor was 100% mucinous in 9 patients, whereas in 4 cases, the lesions consisted of 50% to 90% mucin pools with the remainder being a noncolloid adenocarcinoma component ranging in morphology from bronchioalveolar to acinar, papillary, solid, or mixed patterns. Follow-up ranged from 35 to 128 months. Three patients died, 1 of disease and 2 of unrelated causes. The remaining 10 patients are alive at the time of reporting, 3 with recurrent disease. Immunohistochemical studies showed CK7, CK20, and CDX2 expression in all tumors, whereas TTF-1, surfactant A, and napsin A were not present or were only focally positive in most cases. Analysis showed KRAS mutations in 2 cases. All tumors were negative for ALK gene rearrangement and EGFR mutation. Our study highlights the clinicopathological, immunohistochemical, and molecular features of lung colloid adenocarcinoma and attempts to clarify some misconceptions regarding this rare tumor.

Bordi P, Tiseo M, Barbieri F, et al.
Gene mutations in small-cell lung cancer (SCLC): results of a panel of 6 genes in a cohort of Italian patients.
Lung Cancer. 2014; 86(3):324-8 [PubMed] Related Publications
BACKGROUND: No target therapies are presently available in the treatment of small-cell lung cancer (SCLC). We investigated the presence of potentially drugable mutations in the EGFR, c-MET, BRAF, KRAS, PDGFRa and c-KIT genes in a retrospective series of SCLC from 2 Italian Institutions. Correlations with immunohistochemical, clinical and outcome features were evaluated.
MATERIALS AND METHODS: Genes were studied by direct sequencing of DNA extracted from formalin-fixed paraffin-embedded tissues. Immunohistochemical expression of TTF-1, p63, chromogranin, synaptophysin, CD56 and bcl-2 was assessed.
RESULTS: Samples from 113 SCLC patients were analyzed. All cases were wild-type for BRAF, KRAS, PDGFRa and c-KIT (data available for 82 patients). Two (1.8%) patients were EGFR-mutated (exon 19 delE746-A750 and exon 21 L858R); both were females, non-smoker and had limited disease. Overall survival of EGFR-mutated patients was 21 months as compared to 11 months in wild-type. Five (4.4%) patients were c-MET-mutated (4 on exon 14: 2 R988C, 1 D990N, 1 D102Y; 1 on exon 17 R1166Q); all were smokers, 3 were males and 4 had extensive disease. Their OS was comparable to wild-type cases (12 vs. 11 months). EGFR and c-MET mutations were mutually exclusive. Gene mutations did not correlate with immunophenotype.
CONCLUSIONS: Targetable mutations are uncommon in SCLC. EGFR-mutated patients tended to be female and non-smoker and experienced a prolonged OS suggesting a possible positive prognostic effect. c-MET mutations did not affect survival. Target therapy might be considered in EGFR and c-MET-mutated patients.

Han Y, Yu DP, Zhou SJ, et al.
Associations between clinical characteristics and oncogene expression in patients with non-small cell lung cancer.
Genet Mol Res. 2014; 13(4):8913-24 [PubMed] Related Publications
More than 40 oncogenes associated with non-small cell lung cancer (NSCLC) have been identified with varied gene expression. The correlations between specific clinical characteristics and oncogene expression in NSCLC patients were examined. From October 2011 to September 2012, a total of 60 patients with NSCLC (male:female, 34:24; mean age, 59.5 ± 10.6 years; age range, 31-81 years) were diagnosed and evaluated for treatment with radical resection at a single facility. Eligible patients exhibiting tumor node metastasis (TNM) stage I-III NSCLC confirmed by post-surgical pathology were included. mRNA expression was detected by branched DNA-liquidchip technology (bDNA-LCT) and mutations were detected at EGFR exons 18, 19, 20, and 21, KRAS exons 2 and 3, BRAF and PIK3CA exons 9 and 20. Correlations between gene expression at mutations and clinical characteristics of gender, age, histological type, degree of differentiation, smoking status, immunohistochemical (IHC) evaluation of TTF-1, TNM staging, and discrete age ("nage") were examined. Significant associations were observed between IHC staining for TTF-1 and histological type (P = 0.00001) and with BRAC1, TYMS, RRM1, and TUBB3 expression (P = 0.0187, 0.0051, 0.024, and 0.0238, respectively). Significant cross-correlations were observed between TYMS, BRAC1, TOP2A, STMN1, TUBB3, and RRM1 expression (P < 0.05), but not between EGFR exon 21, KRAS exon 2, and PIK3CA exon 9 expression and any other mutation expression (P > 0.05). Relationships between clinical characteristics and oncogene expression in NSCLC, particularly those of TTF-1 level and smoking status, may be useful indicators of prognosis and development of anti-cancer drug resistance.

Endo T, Yazawa T, Shishido-Hara Y, et al.
Expression of developing neural transcription factors in lung carcinoid tumors.
Pathol Int. 2014; 64(8):365-74 [PubMed] Related Publications
In lung tumors, the association between carcinoids and high-grade neuroendocrine tumors (HGNETs) is controversial. To understand the phenotypic similarities/differences between lung carcinoids and HGNETs, we comparatively investigated the expression of three kinds of developing neural transcription factors (DNTFs: BRN2, TTF1 and ASCL1) and multiple endocrine neoplasia type 1 (MEN1) as well as RB1 and P53 using 18 carcinoids and 16 HGNETs. The DNTFs were expressed in 10 of the 18 carcinoids and in all the HGNETs, while normal neuroendocrine cells, which are considered the major cell origin of lung carcinoids and small cell carcinomas, did not express DNTFs. Both the DNTF(-) and DNTF(+) carcinoids contained typical and atypical carcinoids. All the DNTF(-) carcinoids examined were formed in the bronchial wall. All the MEN1(-) carcinoids examined were classified into the DNTF(-) carcinoids, while all the HGNETs expressed MEN1. This finding suggests that DNTF(-) MEN1(-) carcinoids are unlikely to be precursors of HGNETs. Although the status of RB1 and P53 between carcinoids and HGNETs were apparently different, the DNTF(+) carcinoids of two male patients and one female patient revealed morphologies resembling HGNET cells and relatively high Ki67 indices. Further investigation of DNTF expression in carcinoids might provide important clues to understand the association between carcinoids and HGNETs.

Krawczyk P, Ramlau R, Chorostowska-Wynimko J, et al.
The efficacy of EGFR gene mutation testing in various samples from non-small cell lung cancer patients: a multicenter retrospective study.
J Cancer Res Clin Oncol. 2015; 141(1):61-8 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Testing for the epidermal growth factor receptor (EGFR) gene mutations requires considerable multidisciplinary experience of clinicians (for appropriate patient selection), pathologists (for selection of appropriate cytological or histological material) and geneticists (for performing and reporting reliable molecular tests). We present our experience on the efficacy of routine EGFR testing in various types of tumor samples and the frequency of EGFR mutations in a large series of Polish non-small cell lung cancer (NSCLC) patients.
METHODS: Deletions in exon 19 and substitution L858R in exon 21 of EGFR gene were assessed using real-time PCR techniques in 1,138 small biopsies or cytological specimens and in 1,312 surgical samples.
RESULTS: Out of 2,450 diagnostic samples (containing >10% of tumor cells), the occurrence of EGFR gene mutations was 9%; more frequently in women (13.9%) and adenocarcinoma patients (10%), particularly with accompanying expression of TTF1 (13.0%). The frequency of EGFR gene mutations was similar in cytological and histological specimens, and in primary and metastatic lesions, and did not depend on the percentage of tumor cells and quality of isolated DNA. Cytological or small biopsy, compared to surgical specimens showed lower percentage of tumor cells, with no impact on the quality of real-time PCR assay.
CONCLUSION: Cytological and small biopsy samples with low (10-20%) content of tumor cells and specimens from metastatic lesions are a sufficient source for EGFR mutation testing in NSCLC patients. The incidence of EGFR gene mutations in examined population was similar to those reported in other Caucasian populations.

Vieira T, Antoine M, Ruppert AM, et al.
Blood vessel invasion is a major feature and a factor of poor prognosis in sarcomatoid carcinoma of the lung.
Lung Cancer. 2014; 85(2):276-81 [PubMed] Related Publications
OBJECTIVES: Pulmonary sarcomatoid carcinomas (SC) are highly disseminated types of non-small-cell lung carcinoma. Their prognosis is poor. New therapeutic targets are needed to improve disease management.
MATERIALS AND METHODS: From 1995 to 2013, clinical and survival data from all consecutive patients with surgically treated SC were collected. Pathological and biomarker analyses were performed: TTF1, P63, c-MET and ALK expression (immunohistochemistry), PAS staining, ALK rearrangement (FISH), and EGFR, KRAS, HER2, BRAF, PIK3CA, and MET genes mutations (PCR).
RESULTS: Seventy-seven patients were included. Median age was 61 years (53-69). Histological subtypes were pleomorphic carcinoma (78%), carcinosarcoma (12%), and giant-cell and/or spindle-cell carcinoma (10%). Blood vessel invasion (BVI) was present in 90% of cases. Morphology and immunohistochemistry were indicative of an adenocarcinoma, squamous, and adenosquamous origin in 41.5%, 17% and 11.5%, respectively, 30% remained not-otherwise-specified. KRAS, PIK3CA, EGFR, and MET mutations were found in 31%, 8%, 3%, and 3%, respectively. No tumors had HER2 or BRAF mutations, or ALK rearrangement, whereas 34% had a c-MET positive score. Five-year overall survival (OS) was 29% for the whole population. At multivariate analysis, tumor size <50mm (HR=1.96 [1.04-3.73], p=0.011), no lymph-node metastasis (HR=3.25 [1.68-6.31], p<0.0001), no parietal pleural invasion (HR=1.16 [1.06-1.28], p=0.002), no BVI (HR=1.22 [1.06-1.40], p=0.005), and no squamous component (HR=3.17 [1.48-6.79], p=0.01) were associated with longer OS. Biomarkers did not influence OS.
CONCLUSION: Dedifferentiation in NSCLC could lead to SC and an epithelial subtype component could influence outcome. BVI was present in almost all SCs and was an independent factor of poor prognosis.

Veits L, Schupfner R, Hufnagel P, et al.
KRAS, EGFR, PDGFR-α, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE).
Diagn Pathol. 2014; 9:116 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid.
METHODS: We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-α and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets.
RESULTS: Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-α gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene.
CONCLUSIONS: All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-α gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016.

Shiau CJ, Babwah JP, da Cunha Santos G, et al.
Sample features associated with success rates in population-based EGFR mutation testing.
J Thorac Oncol. 2014; 9(7):947-56 [PubMed] Related Publications
INTRODUCTION: Epidermal growth factor receptor (EGFR) mutation testing has become critical in the treatment of patients with advanced non-small-cell lung cancer. This study involves a large cohort and epidemiologically unselected series of EGFR mutation testing for patients with nonsquamous non-small-cell lung cancer in a North American population to determine sample-related factors that influence success in clinical EGFR testing.
METHODS: Data from consecutive cases of Canadian province-wide testing at a centralized diagnostic laboratory for a 24-month period were reviewed. Samples were tested for exon-19 deletion and exon-21 L858R mutations using a validated polymerase chain reaction method with 1% to 5% detection sensitivity.
RESULTS: From 2651 samples submitted, 2404 samples were tested with 2293 samples eligible for analysis (1780 histology and 513 cytology specimens). The overall test-failure rate was 5.4% with overall mutation rate of 20.6%. No significant differences in the failure rate, mutation rate, or mutation type were found between histology and cytology samples. Although tumor cellularity was significantly associated with test-success or mutation rates in histology and cytology specimens, respectively, mutations could be detected in all specimen types. Significant rates of EGFR mutation were detected in cases with thyroid transcription factor (TTF)-1-negative immunohistochemistry (6.7%) and mucinous component (9.0%).
CONCLUSIONS: EGFR mutation testing should be attempted in any specimen, whether histologic or cytologic. Samples should not be excluded from testing based on TTF-1 status or histologic features. Pathologists should report the amount of available tumor for testing. However, suboptimal samples with a negative EGFR mutation result should be considered for repeat testing with an alternate sample.

Giannakakis A, Karapetsas A, Dangaj D, et al.
Overexpression of SMARCE1 is associated with CD8+ T-cell infiltration in early stage ovarian cancer.
Int J Biochem Cell Biol. 2014; 53:389-98 [PubMed] Related Publications
T-lymphocyte infiltration in ovarian tumors has been linked to a favorable prognosis, hence, exploring the mechanism of T-cell recruitment in the tumor is warranted. We employed a differential expression analysis to identify genes over-expressed in early stage ovarian cancer samples that contained CD8 infiltrating T-lymphocytes. Among other genes, we discovered that TTF1, a regulator of ribosomal RNA gene expression, and SMARCE1, a factor associated with chromatin remodeling were overexpressed in first stage CD8+ ovarian tumors. TTF1 and SMARCE1 mRNA levels showed a strong correlation with the number of intra-tumoral CD8+ cells in ovarian tumors. Interestingly, forced overexpression of SMARCE1 in SKOV3 ovarian cancer cells resulted in secretion of IL8, MIP1b and RANTES chemokines in the supernatant and triggered chemotaxis of CD8+ lymphocytes in a cell culture assay. The potency of SMARCE1-mediated chemotaxis appeared comparable to that caused by the transfection of the CXCL9 gene, coding for a chemokine known to attract T-cells. Our analysis pinpoints TTF1 and SMARCE1 as genes potentially involved in cancer immunology. Since both TTF1 and SMARCE1 are involved in chromatin remodeling, our results imply an epigenetic regulatory mechanism for T-cell recruitment that invites deciphering.

Shanzhi W, Yiping H, Ling H, et al.
The relationship between TTF-1 expression and EGFR mutations in lung adenocarcinomas.
PLoS One. 2014; 9(4):e95479 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To explore the relationship between TTF-1 and EGFR mutations in lung adenocarcinoma tissues to guide clinical treatment timely and effectively.
MATERIALS AND METHODS: we collected 664 tissue samples from patients with histologically confirmed lung adenocarcinoma from May 2010 to April 2013. All tumor tissues were collected prior to administering therapy. TTF-1 was detected by immunohistochemistry and EGFR mutations by DNA direct sequencing. Finally, the correlation between TTF-1 expression and the presence of EGFR mutations was analyzed using χ2 test or Fisher's exact test with SPSS software version 18.0.
RESULTS: Of the 664 lung adenocarcinoma tissue samples, 18 were partially positive for TTF-1 (+-), and 636 were positive for TTF-1 (+) resulting in a total positive rate of 98.49% (+,+-)(including partial positive). In only 10 cases was the TTF-1 negative (-); the negative rate was 1.51%. There were 402 cases without an EGFR mutation and 262 cases with EGFR mutations; the rate of mutations was 39.46%. The location of the EGFR mutation was exon 19 for 121 cases resulting in a mutation rate in exon 19 of 18.22%. The location of the EGFR mutation was exon 21 for 141 cases resulting in a mutation rate in exon 21 of 21.23%. Exon 18 and 20 detected by DNA direct sequencing no mutations.A Fisher's exact test was used to determine the correlation between EGFR mutations and TTF-1 expression.for the whole, TTF-1 positive expression(including partial positive) has correlation with EGFR mutations (p<0.001),especially for Exon 21 expression,the correlation is significant (p = 0.008).
CONCLUSION: In lung adenocarcinomas, positive and partial positive TTF-1 expression has a significant positive correlation with EGFR mutations(exon 19 and 21). In clinical practice, TTF-1 expression combine with EGFR mutations, especially exon 21 mutation can guide clinical treatment timely for lung adenocarcinomas.

Roden AC, García JJ, Wehrs RN, et al.
Histopathologic, immunophenotypic and cytogenetic features of pulmonary mucoepidermoid carcinoma.
Mod Pathol. 2014; 27(11):1479-88 [PubMed] Related Publications
Pulmonary mucoepidermoid carcinoma is an uncommon but distinctive manifestation of mucoepidermoid carcinoma. Pulmonary mucoepidermoid carcinoma occurs in adults and children and can cause diagnostic problems, especially in small biopsies. Few studies have characterized the histologic and immunophenotypic features of pulmonary mucoepidermoid carcinoma. t(11;19)(q21;p13) is considered disease-defining for mucoepidermoid carcinoma; its significance in pulmonary mucoepidermoid carcinoma warrants further study. Forty three pulmonary mucoepidermoid carcinomas were re-reviewed and graded according to the Brandwein grading system for mucoepidermoid carcinoma. Four cases were excluded because of a split opinion between pathology report and re-review. These cases were negative for MAML2 rearrangement by FISH. TTF-1, napsin A, p40 and p63 immunostains were scored: 0 (negative), 1 (1-25% tumor cells), 2 (26-50%), 3 (51-75%) or 4 (>75%). FISH to detect MAML2 rearrangement used a MAML2-11q21 break-apart probe. Thirty nine pulmonary mucoepidermoid carcinoma (4 low, 30 intermediate, 5 high grade) contained mucous, epidermoid and intermediate cells and lacked keratinization and in situ carcinoma of the overlying epithelium. All cases with available gross description (n=22) had a central/endo- or peribronchial location. All 25 cases tested for immunohistochemistry were positive (scores 1-4) for p63; 23 also expressed p40. In six cases, the p63 score was higher than p40. TTF-1 and napsin were uniformly negative in all 25 cases. MAML2 rearrangement was identified by FISH in each of the 24 cases tested (3 low, 19 intermediate, 2 high grade). Clinical history was available in 29 patients (15 men) (median age, 48 years) with follow-up in 24 (median, 8.4 years). Five patients died of unrelated causes; one developed metastatic pulmonary mucoepidermoid carcinoma. In conclusion, features helpful in distinguishing pulmonary mucoepidermoid carcinoma from other lung cancers include its central/endo- or peribronchial location together with the presence of mucous cells, p63 expression, lack of keratinization and MAML2 rearrangement. TTF-1 and napsin are typically not expressed.

Plantinga TS, Heinhuis B, Gerrits D, et al.
mTOR Inhibition promotes TTF1-dependent redifferentiation and restores iodine uptake in thyroid carcinoma cell lines.
J Clin Endocrinol Metab. 2014; 99(7):E1368-75 [PubMed] Related Publications
CONCEPT: Redifferentiation of thyroid carcinoma cells has the potential to increase the efficacy of radioactive iodine therapy in treatment-refractory, nonmedullary thyroid carcinoma (TC), leading to an improved disease outcome. Mammalian target of rapamycin (mTOR) is a key regulator of cell fate affecting survival and differentiation, with autophagy and inflammation as prominent downstream pathways.
METHODS: The effects of mTOR inhibition were studied for its redifferentiation potential of the human TC cell lines BC-PAP, FTC133, and TPC1 by assessment of mRNA and protein expression of thyroid-specific genes and by performance of iodine uptake assays.
RESULTS: In thyroid transcription factor 1 (TTF1)-expressing cell lines, mTOR inhibition promoted redifferentiation of TC cells by the up-regulation of human sodium-iodine symporter mRNA and protein expression. Furthermore, these cells exhibited markedly elevated iodine uptake capacity. Surprisingly, this redifferentiation process was not mediated by autophagy induced during mTOR inhibition or by inflammatory mediators but through transcriptional effects at the level of TTF1 expression. Accordingly, small interfering RNA inhibition of TTF1 completely abrogated the induction of human sodium-iodine symporter by mTOR inhibition.
CONCLUSION: The present study has identified the TTF1-dependent molecular mechanisms through which the inhibition of mTOR leads to the redifferentiation of TC cells and subsequently to increased radioactive iodine uptake.

Micke P, Mattsson JS, Edlund K, et al.
Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer.
Int J Cancer. 2014; 135(9):2206-14 [PubMed] Related Publications
Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n = 355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n = 196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho = 0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p = 0.03] and multivariate COX regression model (HR: 1.9; p = 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.

Wang CX, Liu B, Wang YF, et al.
Pulmonary enteric adenocarcinoma: a study of the clinicopathologic and molecular status of nine cases.
Int J Clin Exp Pathol. 2014; 7(3):1266-74 [PubMed] Free Access to Full Article Related Publications
Pulmonary enteric adenocarcinoma (PEAC), a extremely rare variant of primary invasive adenocarcinoma of the lung, was recognized by the international multidisciplinary classification of lung adenocarcinoma which was proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) published in early 2011. Histologically, PEAC is considered to be mainly composed of tall columnar cells arranged in an irregular glandular cavity or cribriform pattern with extensive central necrosis which show high resemblance to that of intestinal epithelia and colorectal carcinomas. Immunohistochemically, PEAC can not only expresses typical proteins common to lung primaries but is positive for at least one intestinal markers, such as CDX2, cytokeratin (CK) 20, MUC2, therefore, the differentiation of primary PEACs from metastatic colorectal cancers can be challenging. In this study, we report 9 cases of PEAC and a panel of immunohistochemical protein markers of CK7, CK20, thyroid transcription factor 1 (TTF-1), Napsin A, MUC2 and villin was analyzed with the comparison of 20 metastatic colorectal carcinomas (MCRs), and 20 typical primary adenocarcinomas (tPACs). As was expected, CK7 expression was documented in all 9 PEACs and 20 tPCAs while CK20 was significantly more prevalent in adenocarcinoma that originated from colorectal. Additionally, we evaluate the classical mutations of EGFR, KRAS in the 9 cases of PEACs, it turned out that all tumors were EGFR-wild and KRAS-wild types, which confirmed that PEAC has a separate phenotype from usual pulmonary adenocarcinoma.

Nakazawa T, Cameselle-Teijeiro J, Vinagre J, et al.
C-cell-derived calcitonin-free neuroendocrine carcinoma of the thyroid: the diagnostic importance of CGRP immunoreactivity.
Int J Surg Pathol. 2014; 22(6):530-5 [PubMed] Related Publications
In the thyroid, primary neuroendocrine tumors encompass medullary thyroid carcinoma (MTC) and, rarely, other tumors such as paragangliomas. MTCs are derived from C-cells and express calcitonin and neuroendocrine markers. Besides classic MTC, some reports have documented thyroid neuroendocrine tumors, which show no calcitonin expression and raise difficult diagnostic problems. A 76-year-old man presented with a mass in the left thyroid with neither serological calcitonin elevation nor familial history. A thorough clinico-laboratorial study did not disclose any other mass elsewhere. A left hemithyroidectomy was performed, and the histological examination revealed a neuroendocrine carcinoma resembling a paraganglioma-like MTC displaying unequivocal signs of vascular invasion. Immunohistochemically, the tumor cells showed reactivity for chromogranin A, synaptophysin, thyroid transcription factor-1 (TTF-1), paired box gene 8 (PAX8), cytokeratins (AE1/AE3 and CK8/18), and calcitonin gene-related peptide (CGRP) and negativity for calcitonin, carcinoembryonic antigen, TTF-2, thyroperoxidase, and thyroglobulin. In situ hybridization showed that the tumor cells lacked expression for calcitonin and thyroglobulin mRNA. Genetic analysis did not disclose any RET mutation. A diagnosis of C-cell-derived primary neuroendocrine carcinoma of the thyroid without calcitonin expression was made, and the patient remains free of metastasis or recurrence 18 months after surgery.

Carneiro JG, Couto PG, Bastos-Rodrigues L, et al.
Spectrum of somatic EGFR, KRAS, BRAF, PTEN mutations and TTF-1 expression in Brazilian lung cancer patients.
Genet Res (Camb). 2014; 96:e002 [PubMed] Related Publications
Lung cancer is the leading global cause of cancer-related mortality. Inter-individual variability in treatment response and prognosis has been associated with genetic polymorphisms in specific genes: EGFR, KRAS, BRAF, PTEN and TTF-1. Somatic mutations in EGFR and KRAS genes are reported at rates of 15-40% in non-small cell lung cancer (NSCLC) in ethnically diverse populations. BRAF and PTEN are commonly mutated genes in various cancer types, including NSCLC, with PTEN mutations exerting an effect on the therapeutic response of EGFR/AKT/PI3K pathway inhibitors. TTF-1 is expressed in approximately 80% of lung adenocarcinomas and its positivity correlates with higher prevalence of EGFR mutation in this cancer type. To determine molecular markers for lung cancer in Brazilian patients, the rate of the predominant EGFR, KRAS, BRAF and PTEN mutations, as well as TTF-1 expression, was assessed in 88 Brazilian NSCLC patients. EGFR exon 19 deletions (del746-750) were detected in 3/88 (3·4%) patients. Activating KRAS mutations in codons 12 and 61 were noted in five (5·7%) and two (2·3%) patients, respectively. None of the common somatic mutations were detected in either the BRAF or PTEN genes. TTF-1 was overexpressed in 40·7% of squamous-cell carcinoma (SCC). Our findings add to a growing body of data that highlights the genetic heterogeneity of the abnormal EGFR pathway in lung cancer among ethnically diverse populations.

Abbas M, Kramer MW, Spieker T, et al.
Primary mucinous adenocarcinoma of the renal pelvis with carcinoma in situ in the ureter.
J Egypt Natl Canc Inst. 2014; 26(1):51-4 [PubMed] Related Publications
Primary epithelial tumor of the renal pelvis is rare and only 100 cases are reported in the literature [1]. Histological examination of the tumor showed glands, cysts, and papillae lined by pseudostratified columnar epithelium with hyperchromatic nuclei. Scattered signet ring-type cells were also seen floating in large pools of extracellular mucin. Sections from the ureter showed a component of adenocarcinoma in situ. No invasive tumor was identified in ureteric tissue. One case was reported with carcinoma in situ of the ureter (2). Immunohistochemically: The tumor showed positivity for CK7, CK20, CK8/18, GATA-3, MSH-2, MSH-6, MLH-1, Ber-EP4, and S-100-P with focal positivity for CDX-2, weak positivity for PMS-2 and negativity in TTF-1 and Her-2. Molecular pathological analysis revealed microsatellite stability and without mutation in K-ras-gene. Thus, a diagnosis of mucinous adenocarcinoma of the renal pelvis with in situ adenocarcinoma of the ureter was made.

Yamatani C, Abe M, Shimoji M, et al.
Pulmonary adenosquamous carcinoma with mucoepidermoid carcinoma-like component with characteristic p63 staining pattern: either a novel subtype originating from bronchial epithelium or variant mucoepidermoid carcinoma.
Lung Cancer. 2014; 84(1):45-50 [PubMed] Related Publications
BACKGROUND: Our previous study found unique adenosquamous carcinomas (ADSQs) containing a mucoepidermoid carcinoma (MEC)-like component and a characteristic p63 staining pattern. This study focused on these unique ADSQs.
METHODS: Thirty ADSQ cases were studied histologically and by immunohistochemistry for TTF-1 and p63. Of these 30 ADSQs, eight were selected as unique ADSQs. The clinicopathological characteristics of these ADSQs were further studied, and the gene rearrangement of mammalian mastermind-like 2 (MAML2) was investigated by fluorescence in situ hybridization (FISH) for differentiation from pulmonary MEC.
RESULTS: The clinicopathological characteristics between the eight ADSQs and the other ADSQ cases showed no statistically significant differences, except for serum CEA level. Histologically, the eight ADSQs contained varying degrees of the MEC-like component, which consisted of solid nests with mucin-filled cysts or a cribriform-like structure. Immunohistochemically, p63-positive nuclei characteristically encircled the tumor nests, although TTF-1 was completely negative. All unique ADSQs not only had a variable degree of squamous cell carcinoma component in addition to the MEC-like component, but also contained a small tubular adenocarcinoma component in three tumors. FISH analysis revealed no MAML2 gene rearrangement in the eight ADSQs.
CONCLUSIONS: Of the 30 ADSQs investigated in this study, eight contained a MEC-like component with a characteristic p63 basilar staining pattern similar to that of bronchial basal cells. These unique ADSQs shared clinical characteristics with ordinary ADSQs, but clinicopathologically differed from pulmonary ordinary MEC. Therefore, these unique ADSQs may be either a novel ADSQ subtype originating from bronchial epithelium or variant-type MEC.

Baumgart A, Mazur PK, Anton M, et al.
Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model.
Oncogene. 2015; 34(5):578-88 [PubMed] Related Publications
Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in β-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for β-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.

Hes O, de Souza TG, Pivovarcikova K, et al.
Distinctive renal cell tumor simulating atrophic kidney with 2 types of microcalcifications. Report of 3 cases.
Ann Diagn Pathol. 2014; 18(2):82-8 [PubMed] Related Publications
We report 3 cases of primary renal cell tumor simulating atrophic kidney with distinct gross, morphologic, immunohistochemical, and molecular genetic features. The tumors were retrieved out of more than 17 000 renal tumors from the Plzen Tumor Registry. Tissues for light microscopy had been fixed, embedded, and stained with hematoxylin and eosin using routine procedures. The tumors were further analyzed using immunohistochemistry, array comparative genomic hybridization, and human androgen receptor. Analyses of VHL gene and loss of heterozygosity (LOH) 3p were also performed. The patients were 2 women and 1 man, with ages ranging from 29 to 35 years (mean, 31.3 years). Grossly, the neoplasms were encapsulated and round with largest diameter of 3.5 cm (mean, 3.2 cm). Follow-up available for all patients ranged from 2 to 14 years (mean, 8 years). No aggressive behavior was noted. Histologically, akin to atrophic (postpyelonephritic) kidney parenchyma, the tumors were composed of follicles of varying sizes that were filled by eosinophilic secretion. Rare areas contained collapsed follicles. Each follicle was endowed with a small capillary. The stroma was loose, inconspicuous, and focally fibrotic. Two types of calcifications were noted: typical psammoma bodies and amorphous dark-blue stained calcified deposits. Immunohistochemically, tumors were strongly positive for cytokeratins (OSCAR), CD10, and vimentin, with weak immunopositivity for CAM5.2 and AE1-AE3. WT1 and cathepsin K were weakly to moderately focally to diffusely positive. Tumors were negative for cytokeratin 20, carbonic anhydrase IX, parvalbumin, HMB45, TTF1, TFE3, chromogranin A, thyroglobulin, PAX8, and ALK. Only 1 case was suitable for molecular genetic analyses. No mutations were found in the VHL gene; no methylation of VHL promoter was noted. No numerical aberrations were found by array comparative genomic hybridization analysis. LOH for chromosome 3p was not detected. Analysis of clonality (human androgen receptor) revealed the monoclonal nature of the tumor. We describe an unknown tumor of the kidney that (1) resembles renal atrophic kidney or nodular goiter of thyroidal gland; (2) contains a leiomyomatous capsule and 2 types of calcifications; (3) lacks mitoses, atypias, necroses, and hemorrhages and nearly lack Ki-67 positivity; and (4) so far showed benign biological behavior.

Mackinnon AC, Luevano A, de Araujo LC, et al.
Cribriform adenocarcinoma of the lung: clinicopathologic, immunohistochemical, and molecular analysis of 15 cases of a distinctive morphologic subtype of lung adenocarcinoma.
Mod Pathol. 2014; 27(8):1063-72 [PubMed] Related Publications
Lung adenocarcinoma is characterized by marked heterogeneity and may be composed of an admixture of histologic growth patterns, including acinar, papillary, solid, and lepidic (bronchioloalveolar). Tumors displaying a prominent or predominant cribriform architecture are rare and most often confused for metastases from other organs. We report the clinical, histologic, immunohistochemical, and molecular features in 15 primary lung adenocarcinomas with a predominant cribriform histology. All patients were adults between 30 and 80 years of age (median: 64), and all but one reported a history of heavy cigarette smoking. All cases showed a predominant (>70%) cribriform architecture that resembled a variety of tumors arising in other organs, including breast, prostate, ovary, pancreas, uterus, colon, and thyroid. Immunohistochemical stains showed a phenotype consistent with a primary lung tumor (ie, TTF1+/CK7+), with negative results for other markers. Molecular analysis in six cases showed that none harbored an EGFR-activating mutation. KRAS mutation was detected in one case, and an ALK1 and ROS1 gene rearrangement were each detected in an additional two cases. Cribriform adenocarcinomas of the lung represent a distinctive histologic subtype of lung cancer that may be morphologically difficult to differentiate from metastases with a predominant cribriform architecture.

Pelosi G, Haspinger ER, Bimbatti M, et al.
Does immunohistochemistry affect response to therapy and survival of inoperable non-small cell lung carcinoma patients? A survey of 145 stage III-IV consecutive cases.
Int J Surg Pathol. 2014; 22(2):136-48 [PubMed] Related Publications
Whether non-small cell lung carcinoma (NSCLC) unveiled by immunohistochemistry (IHC) has the same clinical outcome as those typed by morphology is still matter of debate. A total of 145 stage III-IV, consecutive inoperable NSCLC patients treated by chemotherapy (133 cases) or EGFR tyrosine kinase inhibitor (12 cases) and including 100 biopsies, 11 surgical specimens, and 34 cytological samples had originally accounted for 120 adenocarcinomas (ADs), 19 squamous cell carcinomas (SQCs), and 6 adenosquamous carcinomas (ADSQCs) by integrating morphology and thyroid transcription factor-1 (TTF1)/p40 IHC. Thirty-two NSCLC-not otherwise specified (NSCLC-NOS) cases were identified by morphology revision of the original diagnoses, which showed solid growth pattern (P < .001), 22 ADs, 5 SQCs, and 5 ADSQCs by IHC profiling (P < .001), and 10 gene-altered tumors (3 EGFR, 5 KRAS, and 2 ALK). While no significant relationships were observed between response to therapy and original, morphology or IHC diagnoses, driver mutations and tumor differentiation by TTF1 expression, AD run better progression-free survival (PFS) or overall survival (OS) than other tumor types by morphology (P = .010 and P = .047) and IHC (P = .033 and P = .046), respectively. Furthermore, patients with NSCLC-NOS confirmed as AD by IHC tended to have poorer OS (P = .179) and PFS (P = .193) similar to that of ADSQC and SQC (P = .702 and P = .540, respectively). A category of less differentiated AD with poorer prognosis on therapy could be identified by IHC, while there were no differences for SQC or ADSQC. The terminology of "NSCLC-NOS, favor by IHC" is appropriate to alert clinicians toward more aggressive tumors.

Rossi G, Mengoli MC, Cavazza A, et al.
Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology.
Virchows Arch. 2014; 464(1):61-8 [PubMed] Related Publications
This study aimed at challenging pulmonary large cell carcinoma (LLC) as tumor entity and defining different subgroups according to immunohistochemical and molecular features. Expression of markers specific for glandular (TTF-1, napsin A, cytokeratin 7), squamous cell (p40, p63, cytokeratins 5/6, desmocollin-3), and neuroendocrine (chromogranin, synaptophysin, CD56) differentiation was studied in 121 LCC across their entire histological spectrum also using direct sequencing for epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and FISH analysis for ALK gene translocation. Survival was not investigated. All 47 large cell neuroendocrine carcinomas demonstrated a true neuroendocrine cell lineage, whereas all 24 basaloid and both 2 lymphoepithelioma-like carcinomas showed squamous cell markers. Eighteen out of 22 clear cell carcinomas had glandular differentiation, with KRAS mutations being present in 39 % of cases, whereas squamous cell differentiation was present in four cases. Eighteen out of 20 large cell carcinomas, not otherwise specified, had glandular differentiation upon immunohistochemistry, with an exon 21 L858R EGFR mutation in one (5 %) tumor, an exon 2 KRAS mutation in eight (40 %) tumors, and an ALK translocation in one (5 %) tumor, whereas two tumors positive for CK7 and CK5/6 and negative for all other markers were considered adenocarcinoma. All six LCC of rhabdoid type expressed TTF-1 and/or CK7, three of which also harbored KRAS mutations. When positive and negative immunohistochemical staining for these markers was combined, three subsets of LCC emerged exhibiting glandular, squamous, and neuroendocrine differentiation. Molecular alterations were restricted to tumors classified as adenocarcinoma. Stratifying LCC into specific categories using immunohistochemistry and molecular analysis may significantly impact on the choice of therapy.

Behrens C, Solis LM, Lin H, et al.
EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma.
Clin Cancer Res. 2013; 19(23):6556-65 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Enhancer of zeste homolog 2 (EZH2) promotes carcinogenesis by epigenetically silencing tumor suppressor genes. We studied EZH2 expression by immunohistochemistry in a large series of non-small cell lung carcinomas (NSCLC) in association with tumor characteristics and patient outcomes.
EXPERIMENTAL DESIGN: EZH2 immunohistochemistry expression was analyzed in 265 normal and premalignant bronchial epithelia, 541 primary NSCLCs [221 squamous cell carcinomas (SCC) and 320 adenocarcinomas] and 36 NSCLCs with paired brain metastases. An independent set of 91 adenocarcinomas was also examined. EZH2 expression was statistically correlated with clinico-pathological information, and EGFR/KRAS mutation status.
RESULTS: EZH2 expression was significantly (P < 0.0001) higher in SCCs compared with adenocarcinomas and in brain metastasis relative to matched primary tumors (P = 0.0013). EZH2 expression was significantly (P < 0.0001) elevated in bronchial preneoplastic lesions with increasing severity. In adenocarcinomas, higher EZH2 expression significantly correlated with younger age, cigarette smoking, and higher TNM stage (P = 0.02 to P < 0.0001). Higher EZH2 expression in adenocarcinoma was associated with worse recurrence-free survival (RFS; P = 0.025; HR = 1.54) and overall survival (OS; P = 0.0002; HR = 1.96). Furthermore, lung adenocarcinomas with low EZH2 levels and high expression of the lineage-specific transcription factor, TTF-1, exhibited significantly improved RFS (P = 0.009; HR = 0.51) and OS (P = 0.0011; HR = 0.45), which was confirmed in the independent set of 91 adenocarcinomas.
CONCLUSION: In lung, EZH2 expression is involved in early pathogenesis of SCC and correlates with a more aggressive tumor behavior of adenocarcinoma. When EZH2 and TTF-1 expressions are considered together, they serve as a prognostic marker in patients with surgically resected lung adenocarcinomas.

Endo T, Kobayashi T
Concurrent overexpression of RET/PTC1 and TTF1 confers tumorigenicity to thyrocytes.
Endocr Relat Cancer. 2013; 20(6):767-76 [PubMed] Free Access to Full Article Related Publications
A variant located on 14q13.3 nearest to thyroid transcription factor-1 (TTF1) predisposes individuals to thyroid cancer, but whether this variant is related to the RET/PTC rearrangement associated with human papillary thyroid carcinomas (PTCs) is unknown. The aims of this study were to investigate the effects of RET/PTC1 on the expression of thyroid-specific genes in thyrocytes and their relationship with malignant transformation of the thyrocytes. In the absence or presence of TSH, an extracellular signal-regulated kinase was phosphorylated in FRTL5 cells that stably expressed RET/PTC1, and these cells grew independently of TSH. FRTL (RET/PTC1) cells produced 566% more thyroglobulin mRNA and 474% more Na+/I- symporter mRNA than did the control FRTL (pcDNA) cells. FRTL (RET/PTC1) cells expressed 468% more Ttf1 mRNA than did FRTL (pcDNA) cells, but these two cell types did not differ significantly with respect to Pax8 or Ttf2 mRNA levels. When FRTL (RET/PTC1) cells and FRTL (pcDNA), cells were injected into each of nine nude mice, each mouse developed a single tumor at the site of FRTL (RET/PTC1) cell injection; in contrast, tumor formation never occurred at sites of FRTL (cDNA) cells injection. Tumors resulting from FRTL (RET/PTC1) cells retained (125)I-uptake activity; moreover, the cells invaded into surrounding skeletal muscle. When overexpression of Ttf1 in FRTL (RET/PTC1) cells was silenced, the cells completely lost their tumorigenic potential. Exogenous TTF1 cDNA enhanced the tumorigenicity of BHP18-21v cells, human PTC cells that express RET/PTC1, in nude mice. These results indicated that concurrent overexpression of RET/PTC1 and TTF1 confers tumorigenicity to FRTL5 and BHP18-21v cells in nude mice.

Warth A, Penzel R, Lindenmaier H, et al.
EGFR, KRAS, BRAF and ALK gene alterations in lung adenocarcinomas: patient outcome, interplay with morphology and immunophenotype.
Eur Respir J. 2014; 43(3):872-83 [PubMed] Related Publications
Numerous studies have been published on single aspects of pulmonary adenocarcinoma (ADC). To comprehensively link clinically relevant ADC characteristics, we evaluated established morphological, diagnostic and predictive biomarkers in 425 resected ADCs. Morphology was reclassified. Cytokeratin-7, thyroid transcription factor (TTF)1, napsin A, thymidylate synthase and excision repair cross-complementing rodent repair deficiency complementation group-1 expression, anaplastic lymphoma kinase rearrangements as well as epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) and v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutations were analysed. All characteristics were correlated with clinical and survival parameters. Morphological ADC subtypes were significantly associated with smoking history and distinct patterns of diagnostic biomarkers. KRAS mutations were prevalent in male smokers, while EGFR mutations were associated with female sex, nonsmoking and lepidic as well as micropapillary growth patterns. TTF1 expression (hazard ratio (HR) for overall survival 0.61, p=0.021) and BRAF mutations (HR for disease-free survival 2.0, p=0.046) were found to be morphology- and stage-independent predictors of survival in multivariate analysis. Adjuvant radio-/chemotherapy, in some instances, strongly impacted on the prognostic effect of both diagnostic and predictive biomarkers. Our data draw a comprehensive picture of the prevalence and interplay of established histological and molecular ADC characteristics. These data will help to develop time- and cost-effective diagnostic and treatment algorithms for ADC.

Remo A, Zanella C, Pancione M, et al.
Lung metastasis from TTF-1 positive sigmoid adenocarcinoma. pitfalls and management.
Pathologica. 2013; 105(2):69-72 [PubMed] Related Publications
The lung is a frequent site of metastatic involvement, and in many cases the differential diagnosis between a metastasis and a primary carcinoma is a substantial question. TTF-1 is considered as a reliable marker for differential diagnosis in distinguishing primary lung carcinoma and metastasis, especially when dealing with an adenocarcinoma or a large-cell carcinoma. It was generally thought that adenocarcinomas arising in the gastrointestinal tract do not express TTF-1. Recently, it has been reported that a small percentage (1.8%-5.8%) of intestinal adenocarcinoma TTF-1 positive show differences in sensitivity/specificity depending on the antibody clones. We report a case of lung localization of a TTF-1 positive adenocarcinoma in a patient with a history of colon adenocarcinoma. Based on the current results and previous reports, we propose the following criteria for diagnosing lung metastasis from TTF-1 positive intestinal adenocarcinoma. 1) Clinical features and anamnestic history are diagnostic milestones, and provide very important information as a prognostic parameter of primary carcinoma and the time interval between the two localizations (primary and metastasis). 2) The histologic features are compatible with an enteric differentiation. 3) TTF-1 must be tested in the primary carcinoma. 4) In lung lesions, in association with TTF-1, it could be useful to test other immunohistochemical markers such as CDX-2 and NapsinA. 5) Testing other immunohistochemical or molecular markers in either lesion is not very useful. Heterogeneity between primary and metastatic lesions has been reported in the literature. Application of the above-mentioned criteria would simplify diagnosis of lung metastases from TTF-1 positive intestinal adenocarcinoma.

Vallee A, Sagan C, Le Loupp AG, et al.
Detection of EGFR gene mutations in non-small cell lung cancer: lessons from a single-institution routine analysis of 1,403 tumor samples.
Int J Oncol. 2013; 43(4):1045-51 [PubMed] Free Access to Full Article Related Publications
Activating mutations of the epidermal growth factor receptor (EGFR) in lung tumors are associated with a dramatic response to tyrosine kinase inhibitors. Therefore, routine analysis of pathological specimens is mandatory in clinical practice. We have prospectively tested tumors from Caucasian lung tumor patients between January 2010 and June 2012. DNA was extracted from formalin-fixed paraffin-embedded tissues following macrodissection. The p.L858R substitution was assessed by allele-specific PCR and exon 19 deletions by PCR and DNA fragment analysis. Using a robust process from patient sampling to screening methods, we analyzed samples from 1,403 patients. The EGFR status could be successfully determined for 1,322 patients. EGFR mutations were detected in 179 (13.5%) patients, with female and adenocarcinoma histology predominance. Mutated patients were significantly older than non-mutated patients. Similar mutation rates were obtained with primary tumors and metastases, and with surgical resection, bronchial biopsies, CT-guided needle biopsies and transbronchial needle aspiration. The sensitivity of our assays allowed us to detect EGFR mutations in samples poor (<10%) in tumor cells. Finally, the mutation rate was much higher in tumors expressing the TTF-1 antigen (145/820; 17.7%) than in TTF-1 negative tumors (3/218; 1.4%). The results obtained through routine analysis of more than 1,300 samples indicated that all types of specimen can be analyzed without any significant bias. TTF-1 immunostaining may be used to predict negative EGFR mutation status.

Mussazhanova Z, Miura S, Stanojevic B, et al.
Radiation-associated small cell neuroendocrine carcinoma of the thyroid: a case report with molecular analyses.
Thyroid. 2014; 24(3):593-8 [PubMed] Related Publications
BACKGROUND: Neuroendocrine tumor (NET) of the thyroid other than medullary carcinoma is extremely rare. We describe here a case of calcitonin-negative small cell neuroendocrine carcinoma (SCNEC), which occurred in a thyroid gland that had previously been irradiated at high dose (60 Gy) for pharyngeal cancer, with molecular analyses for follicular cell origin.
PATIENT FINDINGS: The tumor cells were small with fine chromatin, inconspicuous nucleoli, and inapparent cytoplasm, and showed neuroendocrine architectures such as palisading, rosettes, and trabeculae. Mitotic figures were numerous exceeding 10 mitoses per 10 high-power fields. The tumor cells invaded into several vessels and metastasized to regional lymph nodes. Immunohistochemically, the tumor cells were strongly positive for neuroendocrine markers and thyroglobulin (Tg), a marker of thyroid follicular cells but negative for calcitonin and carcinoembryonic antigen (CEA). Expression of Tg and thyrotropin receptor (TSHR) were confirmed by quantitative real-time polymerase chain reaction (RT-PCR). Ki-67 labeling index was more than 70% in the tumor cells. Taken together, the tumor was diagnosed as SCNEC of the thyroid. Genetic analyses also revealed microsatellite abnormalities of the phosphatase and tensin homolog (PTEN) gene, suggesting that functional loss of PTEN contributes to carcinogenesis.
CONCLUSIONS: This is the first report describing a SCNEC of the thyroid with molecular analyses that provide evidence for a follicular epithelial origin.

Mu D
The complexity of thyroid transcription factor 1 with both pro- and anti-oncogenic activities.
J Biol Chem. 2013; 288(35):24992-5000 [PubMed] Free Access to Full Article Related Publications
After the original identification of thyroid transcription factor 1 (TTF-1 or NKX2-1) biochemical activity as a transcriptional regulator of thyroglobulin in 1989, the bulk of the ensuing research has concentrated on elucidating the roles of NKX2-1 in the development of lung and thyroid tissues. Motivated by its specific expression pattern, pathologists adopted the NKX2-1 immunoreactivity to distinguish pulmonary from nonpulmonary nonthyroid adenocarcinomas. Interestingly, the concept of NKX2-1 as an active participant in lung tumorigenesis did not take hold until 2007. This minireview contrasts the recent advancements of NKX2-1-related observations primarily in the realm of pulmonary malignancies.

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