Prognostic Impact Of Ttf
1. Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Republic of Korea2. Department of Internal Medicine, National Army Capital Hospital, The Armed Forces Medical Command, Sungnam, Gyeonggi-Do, Republic of Korea* JH Kim and HS Kim equally contributed to this work.
Corresponding author: Jung Han Kim, MD, PhD. Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea. E-mail: harricilcom, harricilor.krMore
Citation:J Cancer
Correlation Of Napsin A And Ttf
Table IV shows the phenotype of lung adenocarcinoma by immunohistochemical staining. Combining napsin A and TTF-1 resulted in sensitivity to lung adenocarcinoma increasing to 91.0% , whereas the specificity was 80.4% . Using Spearmans correlation coefficient analysis, the expression of napsin A significantly correlated with TTF-1 in lung adenocarcinomas , as well as in moderately and well-differentiated adenocarcinomas . Napsin A expression also positively correlated with TTF-1 in poorly differentiated adenocarcinomas, but without significance .
Papillary Thyroid Carcinoma With Classic Architecture And Reduced Thyroglobulin Expression
PTCs often display variable cytomorphological features. In solid, spindle, clear cell, and diffuse sclerosing variants, expression for thyroglobulin can be variable . Reduced or absent staining can also feature cribriform-morular and rarely in columnar cell variant of PTCs. Nevertheless, absence of thyroglobulin expression in a papillary thyroid carcinoma requires further assessment first concerning the influence of less adequate preanalytical conditions and, second, for the possibility of a genetic defect, either somatic or constitutional, that compromise the integrity of the thyroglobulin as a protein. Combined reactivity for monoclonal PAX8 and TTF1 antibodies often support the thyroid follicular epithelial origin in the appropriate cytomorphological and clinical context . However, the demonstration of thyroperoxidase and T4 expression or application of in situ hybridization to detect thyroglobulin RNA is also helpful in the identification of follicular differentiation.
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Study Selection And Characteristics
Seventeen studies published between 1999 and 2012 were eligible for this systematic review with meta-analysis. All reported the prognostic value of TTF-1 status for survival in NSCLC patients. The total number of patients included was 2,235, ranging from 57 to 496 patients per study . The major characteristics of the 17 eligible publications are reported in Table 1.
These publications followed several different patient cohorts. The NSCLC studies considered either all lung cancer subtypes and adenocarcinomas . Three studies had information for stages I, 4 for stage IIIb-IV disease. All 17 studies used immunohistochemistry to evaluate TTF-1 expression in NSCLC. Among the 17 studies evaluating TTF-1 expression in NSCLC, 7 studies were performed in Asian populations, and the remaining 10 studies followed European or American patients. Only one of the 17 studies identified TTF-1 overexpression as an indicator of poor prognosis, 4 studies showed no statistically significant impact of VEGF overexpression on survival, and the other 12 studies showed for favorable significance. The proportion of patients exhibiting TTF-1 overexpression in individual studies ranged from 16% to 89%.
Data Extraction And Quality Assessment
The final articles included were assessed independently by two reviewers . Data retrieved from the reports included first author, publication year, patient source, histology, disease stage, test method, TTF-1 positive and survival data . If data from any of the above categories were not reported in the primary study, items were treated as ânot applicableâ. We did not contact the author of the primary study to request the information.
Table 1
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Papillary Thyroid Carcinoma With Desmoid
PTCs with fibromatosis/fasciitis-like stroma are now designated as PTCs with desmoid-type fibromatosis . These are biphasic tumors that are composed of abundant cellular PTC component admixed with spindle cells with benign stroma resembling nodular fasciitis or desmoid-type fibromatosis .
The stromal component expresses nuclear beta-catenin and cytoplasmatic smooth muscle actin and lacks cytokeratins and TTF1. Nuclear detection of SOX11 can be an alternative diagnostic tool for evaluating tumors where nuclear expression for -catenin is ambiguous .
PTCs with fibromatosis/fasciitis-like stroma should be distinguished from anaplastic thyroid carcinomas. Lack of nuclear beta-catenin expression in the stroma, lack of follicular epithelial differentiation, positivity for PAX8 and/or TTF1, and presence of increased proliferative activity are features that can help in the distinction of anaplastic thyroid carcinomas.
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Thyroid Tumor With Neoplastic Solid Cell Nest Features
Solid cell nests are remnants of ultimobranchial body remnants . They are composed of main cells that are positive for p63, p40, high- and low-molecular-weight cytokeratins, galectin 3, Bcl-2, CEA, TTF1 , and GATA3 and are negative for monoclonal PAX8 . C cells can sometimes be admixed with main cells of solid cell nests.
Hyperplastic solid cell nests are not unusual in thyroids removed due to other causes, and giant solid cell nests have also been documented . Chan and Rosai expanded on the group of tumors designated as tumors of the neck showing thymic or related branchial pouch differentiation that may be related to solid cell nest or thymus origin . To date, a pure solid cell nest tumor has not been defined. However, exceptional thyroid neoplasms with cytomorphological and immunohistochemical features of main cells of solid cell nests have also been reported mimicking a basaloid neoplasm . These basaloid cells disclosed expression of markers typical of the main cells of solid cell nests favoring a histogenesis link between this tumor and solid cell nests and also supporting a pathogenesis link between PTC and ultimobranchial body remnants . In such a case, the possibility of a metastatic disease should be excluded after exhaustive search for a primary neoplasm elsewhere.
Fig. 5
Villous Variant Of Papillary Thyroid Carcinoma
This is an extremely rare cytomorphological variant of PTC that was reported in a patient with Marfan syndrome due to FBN1 gene mutation . The term villous is proposed by Winer et al. because of the tumor growth characterized by prominent long villous fronds that were unassociated with tall cell or columnar cell features .
The tumor can simulate a metastatic carcinoma however, the demonstration of thyroglobulin, TTF1, and PAX8 confirms the thyroid follicular origin. At a molecular level, the reported tumor harbored pathogenic BRAFV600E mutation. Winer et al. hypothesized that the presence of BRAFV600E mutation in the background of TGF–related epithelial-to-mesenchymal transition with active phospho-SMAD signaling may have resulted in this peculiar morphology . Although the data is sparse, the distinction of villous variant of PTC is of clinical interest as it may be a harbinger of Marfan syndrome.
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Patient Selection And Tissue Sample Collection
All patients with lung cancer in this study were from Changhai Hospital, Shanghai, P.R. China, during the period 2007 and 2008. The pathological tissue specimen and clinical data for each patient were colleted prior to treatment. The clinical data included age, gender, smoking history, performance status , histopathological diagnosis, grade of tumor differentiation, tumor stage, primary tumor size and nodal metastasis. Histological subclassification was carried out according to the World Health Organization classification. PS was estimated using the Eastern Cooperative Oncology Group scale. Tumor stage was defined according to the International Union Against Cancer classification. In total, 324 patients with primary lung cancer and 27 patients with metastatic lung cancer met our study criteria.
Among the 324 patients, 222 cases were male and 102 cases, female , and the median age was 61 years . A total of 145 patients had a history of smoking and 264 patients had symptoms when first diagnosed, such as cough, expectoration, hemoptysis, chest pain and fever. Adenocarcinoma was the most common tumor type in the patients , followed by squamous cell , small-cell , adenosquamous cell and large-cell carcinoma . A total of 119 patients had stage III disease and the remaining 205 patients had stage IIIIV disease. There were 200 patients with nodal metastasis and 284 patients with a primary tumor > 3 cm when diagnosed.
Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License . Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor. The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
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Citation Doi & Article Data
Citation:DOI:Yuranga WeerakkodyRevisions:see full revision historySystem:
- Thyroid transcription factor 1
- Thyroid transcription factor 1
Thyroid transcription factor 1 refers to a homeodomain-containing nuclear transcription factor that belongs to the Nkx2 gene family encoded by a gene located on chromosome 14q13.
It is expressed in the forebrain, thyroid and lung tissues. The presence of TTF-1 protein on a tissue sample is useful in the diagnosis of lung cancer and can be expressed in up to 90% of pulmonary small cell carcinoma but usually not in squamous cell carcinoma.
It is rarely expressed in some primary extrapulmonary tumors 1.
Some publications suggest its “overexpression” may result in a more favorable overall prognosis 4.
See also
Intrathyroidal Parathyroid Neoplasms With Follicular Growth
Parathyroid adenoma and carcinoma can manifest with an intrathyroidal nodule . Intrathyroidal parathyroid adenomas are frequently misdiagnosed as follicular lesion on FNAB specimens. Intrathyroidal parathyroid adenoma must not be interpreted as an evidence of parathyroid carcinoma. The diagnosis of intrathyroidal parathyroid carcinoma requires demonstration of invasive growth.
Positivity for chromogranin A, GATA3, GCM2, and PTH can distinguish parathyroid origin . One should also be aware that parathyroid proliferations can display aberrant reactivity for calcitonin and CGRP therefore, positivity for GATA3 and GCM2 and negativity for monoclonal CEA and TTF1 can be used to confirm the parathyroid origin .
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Search Strategy And Study Selection
The electronic databases PubMed, Embase, and CNKI were searched for studies to include in our meta-analysis. An upper date limit of Jan 31, 2012 was applied we used no lower date limit. Searches included the terms âlung cancerâ, âTTF-1â, âthyroid transcription factor 1â, and âprognosisâ. We also reviewed the Cochrane Library for relevant articles. The references reported in the identified studies were also used to complete the search.
Studies eligible for inclusion in this meta-analysis met the following criteria: measure TTF-1 expression in the primary lung cancer tissue with IHC or other methods provide information on survival have a follow up time exceeding 5 years and When the same author reported results obtained from the same patient population in more than one publication, only the most recent report, or the most complete one, was included in the analysis. Two reviewers independently determined study eligibility. Disagreements were resolved by consensus.
Mixed Medullary And Follicular Thyroid Carcinoma
Mixed medullary and follicular thyroid carcinomas are rare primary malignant thyroid neoplasms that are composed of two distinct tumor components with distinct morphological and immunohistochemical evidence of C cell and follicular cell lineages within the same lesion . The proportion of each of the two lineages can vary, and there is no well-established cutoff point . The existence of synchronous medullary thyroid carcinoma and follicular cell-derived carcinomas in close proximity but without intermixing is considered collision tumors, and should not be classified as MMFTC .
The histology of the medullary thyroid carcinoma component of MMFTC is not different than that of the conventional medullary thyroid carcinoma . The follicular cell component is usually represented by the follicular variant of PTC . However, rare examples of conventional PTC, follicular thyroid carcinoma, oncocytic or poorly differentiated carcinoma, and undifferentiated thyroid carcinoma have been documented . Metastases can originate from both tumor components however, this can also consists of one component .
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Study Populationprimary Lung Cancers
The present study included 665 resected primary lung cancers from 657 individuals originally included in three independent unselective cohorts with tumor tissue available and evaluable on tissue microarrays .
The first cohort consisted of 355 tumors from 351 patients who were surgically treated at the Uppsala University Hospital, Uppsala, Sweden, from 2006 to 2010., The second cohort consisted of 207 tumors from 205 patients who were prospectively included in the Southern Swedish Lung Cancer Study and surgically treated at the Skåne University Hospital, Lund, Sweden, from 2005 to 2011. One case diagnosed and reported as primary lung SCC in our previous publications on this cohort has been proven with further IHC staining to be a pulmonary metastasis of the patients previous urothelial carcinoma and hence excluded. The third cohort consisted of 115 lung cancers from 113 patients included in the population-based prospective Malmö Diet and Cancer Study, and surgically treated at the Skåne University Hospital, Lund, Sweden, from 1996 to 2010. Twelve of these cases were also included in the Southern Swedish Lung Cancer Study, and each of these cases was only included once in the present study.
Napsin A A New Marker For Lung Adenocarcinoma Is Complementary And More Sensitive And Specific Than Thyroid Transcription Factor 1 In The Differential Diagnosis Of Primary Pulmonary Carcinoma: Evaluation Of 1674 Cases By Tissue Microarray
Bradley M. Turner, Philip T. Cagle, Irma M. Sainz, Junya Fukuoka, Steven S. Shen, Jaishree Jagirdar Napsin A, a New Marker for Lung Adenocarcinoma, Is Complementary and More Sensitive and Specific Than Thyroid Transcription Factor 1 in the Differential Diagnosis of Primary Pulmonary Carcinoma: Evaluation of 1674 Cases by Tissue Microarray. Arch Pathol Lab Med 1 February 2012 136 : 163171. doi:
Context.Differentiation of nonsmall cell carcinoma into histologic types is important because of new, successful therapies that target lung adenocarcinoma . TTF-1 is a favored marker for lung ACA but has limited sensitivity and specificity. Napsin A is a functional aspartic proteinase that may be an alternative marker for primary lung ACA.
Objectives.To compare Nap-A versus TTF-1 in the typing of primary lung carcinoma and the differentiation of primary lung ACA from carcinomas of other sites.
Design.Immunohistochemistry for Nap-A and TTF-1 was performed on tissue microarrays of 1674 cases of carcinoma: 303 primary lung ACAs , 200 primary squamous cell lung carcinomas , 52 primary small cell carcinomas of the lung , and carcinomas of the kidney , thyroid , biliary , bladder , breast , colon , liver , ovaries , pancreas , prostate , stomach , and uterus . Cases were evaluated against a negative control as negative, weak positive, and strong positive.
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Spindle Cell Follicular Tumors
Follicular nodular disease, follicular adenoma, PTC, FTC, and medullary thyroid carcinoma can disclose focal or diffuse spindle cell phenotype . The differential diagnosis between these tumors must follow the criteria of the respective non-spindle cell variants.
Spindle cell variants of PTC are composed of tumor cells that are arranged in bundles . Frequent nuclear grooves and less frequently pseudoinclusions also feature such tumors . Follicular structures may be seen at the periphery of the tumor.
Fig. 10
Spindle cell variant of papillary thyroid carcinoma showing spindle cells with typical PTC nuclei . Meningioma-like follicular adenoma , the typical arrangement of spindle to ovoid cells in a whorled pattern may give the impression one is dealing with a vascular tumor. Pericytic-like follicular adenoma is characterized by a proliferation of spindle follicular cells concentrically arranged around vessels the follicular nature of the tumor cells could be confirmed by the positivity for thyroglobulin , thyroperoxidase, TTF1 and cytokeratins but negativity for calcitonin and CD31. PTC with fibromatosis/fasciitis-like stroma with both stromal and PTC component
The cellular origin of spindle cell tumors in the thyroid gland should be confirmed using immunohistochemistry. Combined expression for PAX8 and TTF1 distinguishes follicular epithelial origin. Thyroglobulin expression may be only focally observed in some cases.
Comparison With Whole Tumor Sections
From the clinical setting, a whole tumor section stained with TTF-1 clone 8G7G3/1 was available for 123 of the metastases to the lungs . The staining was negative in both TMA and whole tumor section in 118 of these cases and positive in both in one metastasis of colorectal cancer . In one metastasis of urothelial carcinoma, the staining was positive on TMA while negative on the whole tumor section . In another metastasis of urothelial carcinoma and in two metastases of colorectal cancer, there was focal TTF-1 positivity on the whole tumor section while the staining was negative on TMA.
Additional staining of a whole tumor section with clone SPT24 was performed for 18 pulmonary metastases positive for any TTF-1 clone on TMA but with less than 50% positive tumor cells for all clones . In 11 of these, the score was the same on the whole tumor section as on TMA, while the score on the whole section was one step higher for five cases and one or two steps lower for two cases.
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