Thyroid Transcription Factor-1 Positivity Research Articles

TTF-1 is a highly sensitive but not fully specific marker for pulmonary and thyroidal cancer: a tissue microarray study evaluating more than 17,000 tumors from 152 different tumor entities.

Thyroid transcription factor 1 (TTF-1) immunohistochemistry (IHC) is routinely used for the distinction of primary pulmonary adenocarcinomas. However, TTF-1 can also occur in other malignancies. A tissue microarray containing 17,772 samples from 152 different tumor types was analyzed. Napsin-A, CK20, SATB2, FABP1, and Villin-1 IHC data were available from previous studies. TTF-1 staining was seen in 82 of 152 tumor categories including thyroidal cancers (19-100%), adenocarcinomas (94%), neuroendocrine tumors (67%) of the lung, small cell neuroendocrine carcinomas (71-80%), mesenchymal tumors (up to 42%), and thymomas (39%). Comparative analysis of TTF-1 and Napsin-A revealed a sensitivity/specificity of 94%/86% (TTF-1), 87%/98% (Napsin-A), and 85%/99.1% (TTF-1 and Napsin-A) for the distinction of pulmonary adenocarcinomas. Combined analysis of TTF-1 and enteric markers revealed a positivity for TTF-1 and at least one enteric marker in 22% of pulmonary adenocarcinomas but also a TTF-1 positivity in 6% of colorectal, 2% of pancreatic, and 3% of gastric adenocarcinomas. TTF-1 is a marker of high sensitivity but insufficient specificity for pulmonary adenocarcinomas. A small fraction of TTF-1-positive gastrointestinal adenocarcinomas represents a pitfall mimicking enteric-type pulmonary adenocarcinoma. Combined analysis of TTF-1 and Napsin-A improves the specificity of pulmonary adenocarcinoma diagnosis.

Gastric-Type Expression Signature in Hepatocellular Carcinoma.

It is known that V-set and immunoglobulin domain containing 1 (VSIG1) is a cell-cell adhesion molecule that can serve as an indicator of better survival in patients with gastric cancer. Its interaction with cytoplasmic thyroid transcription factor 1 (TTF-1) has been hypothesized to characterize gastric-type HCC, but its clinical importance is far from understood. As VSIG1 has also been supposed to be involved in the epithelial-mesenchymal transition (EMT) phenomenon, we checked for the first time in the literature the supposed interaction between VSIG1, TTF-1, and Vimentin (VIM) in HCCs. Immunohistochemical (IHC) stains were performed on 217 paraffin-embedded tissue samples that included tumor cells and normal hepatocytes, which served as positive internal controls. VSIG1 positivity was seen in 113 cases (52.07%). In 71 out of 217 HCCs (32.71%), simultaneous positivity for VSIG1 and TTF-1 was seen, being more specific for G1/G2 carcinomas with a trabecular architecture and a longer OS (p = 0.004). A negative association with VIM was revealed (p < 0.0001). Scirrhous-type HCC proved negative for all three examined markers. The present paper validates the hypothesis of the existence of a gastric-type HCC, which shows a glandular-like architecture and is characterized by double positivity for VSIG1 and TTF-1, vimentin negativity, and a significant OS.

Abstract 5221: TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading

Abstract Background: Thyroid transcription factor 1 (TTF-1) is expressed in 70% to 80% of lung adenocarcinomas (LUAD). Several papers revealed that TTF-1 expression is associated with better patient outcomes independent of the tumor stage. However, it is unknown whether the prognostic impact of TTF-1 only results from a different growth pattern (tumor grading) or is independently associated with a biologically more aggressive phenotype. Thus, we analyzed a large bi-centric cohort of LUAD to assume the true prognostic value of TTF-1 in relation to the tumor grade. Methods: We collected a large, real-life cohort of 447 patients with completely resected LUAD from two large-volume German lung cancer centers. TTF-1 status, evaluated by IHC, and tumor grading were correlated with clinical, pathologic, and molecular data, as well as patient outcomes. Kaplan-Meier curves were used for comparison of TTF-1 status and different tumor grades in terms of the DFS. The impact of TTF-1 was measured by univariate and multivariate Cox regression. Finally, a causal graph analysis was performed to identify and account for potential confounders to improve the statistical estimation of the predictive power of TTF-1 expression for DFS in comparison to the tumor grade. Results: Kaplan-Meier curves revealed that TTF-1 positivity is associated with longer DFS independent of tumor grade, whereas a strong association of DFS with the tumor grade is observed only in TTF-1-positive patients. In univariate analysis, TTF-1 positivity was associated with significantly longer DFS (median log HR -0.83 [-1.43; -0.20]; p=0.018), whereas higher tumor grade showed a non-significant association with shorter DFS (median log HR 0.30 [-0.58; 1.60]; p=0,62 for G1 to G2 and 0.68 [-0.24; 1.89]; p=0,34 for G2 to G3). In multivariate analysis, TTF-1 positivity resulted in a significantly longer DFS (median log HR -0.65 [-1.13; -0.09]; p=0.05) independent of all other parameters, including tumor grade. Applying the adjustment sets suggested by the causal graph analysis, the superiority of TTF-1 (median log HR -0.86 [-1.25; -0.41]) over tumor grade (median log HR 0.31 [-0.32; 1.30]/0.61[-0.07; 1.65]) in terms of prognostic power was confirmed. Conclusion: This study draws three important conclusions: Firstly, it indicates that the prognostic power of tumor grade is limited to TTF-1-positive patients. Secondly, it underlines the independent prognostic value of TTF-1 expression for DFS regardless of tumor grade. Finally, our analyses reveal that the effect size of TTF-1 surpasses that of tumor grade. To transfer the results directly into the clinical area, we recommend distinguishing between TTF-1-positive and TTF-1-negative LUADs in the pathological report. Tumor grading should only be applied to TTF-1-positive LUADs (TTF-1+/G1-3). TTF-1-negative LUADs should either not be graded or always be classified as high-grade (TTF-1-/G3). Citation Format: Simon Schallenberg, Gabriel Dernbach, Mihnea Dragomir, Georg Schlachtenberger, Kyrill Boschung, Corinna Friedrich, Kai Standvoss, Lukas Ruff, Philipp Anders, Christian Grohe, Winfried Randerath, Sabine Merkelbach-Bruse, Alexander Quaas, Matthias Heldwein, Ulrich Keilholz, Khosro Hekmat, Jens Rückert, Reinhard Büttner, David Horst, Frederick Klauschen, Nikolaj Frost. TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5221.

Disease control in patients with non-small cell lung cancer using pemetrexed: Investigating the best treatment strategy.

Pemetrexed (PEM) is the primary chemotherapy for non-small cell lung cancer (NSCLC), showing potential for long-term disease stability in certain cases. However, studies examining disease control with PEM therapy are lacking. This study aimed to pinpoint clinical traits in patients with NSCLC responding well to PEM therapy, predict factors influencing disease control, and suggest optimal treatment approaches. A retrospective analysis of patients with NSCLC treated with PEM was performed to compare patients who achieved disease control after treatment with those who did not. Of 73 patients, 56 (76.7%) achieved disease control with PEM therapy. In the disease control group, a significantly higher proportion of patients exhibited good performance status (PS) and received PEM doses without reduction after the second cycle. Multivariate analysis identified bevacizumab (Bev) noncompliance, PEM dose reduction, and thyroid transcription factor-1 (TTF-1) negativity as significant independent risk factors for disease progression during PEM therapy. Additionally, overall survival was significantly longer in the disease control group (p < 0.001). Our findings indicated that maintaining the dose of PEM after the second treatment cycle in patients with NSCLC, along with concurrent use of Bev and the presence of TTF-1 positivity, could enhance disease control rates and extend survival.

Discrepancies Between Morphological and Immunohistochemical Classifications Are Associated With Prognoses and Subtypes of Lung Cancer.

Immunohistochemical (IHC) staining has been routinely used to distinguish adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of the lungs; however, it is challenging to obtain an accurate diagnosis, especially for cases with discrepancies between IHC and hematoxylin and eosin (H&E) staining results. This study aimed to clarify the clinicopathological characteristics of these discrepant cases. Tissue microarray specimens from 321 patients with ADC and SCC were used for H&E and IHC staining of thyroid transcription factor 1 (TTF-1), Napsin A, cytokeratin 5/6 (CK5/6), p40, and p63. The pathological diagnosis was made based on (1) H&E, (2) IHC, and (3) both H&E and IHC results. Discrepant cases were defined as those with different diagnoses based on the H&E and IHC results. A total of 32 (10%) discrepant cases were identified. ADC (3.9%) showed fewer discrepant cases than SCC (51%). Discrepant cases of ADC had a significantly higher proportion of poorly differentiated tumors and subtypes of solid and invasive mucinous ADC, and they also had shorter overall and disease-free survival than concordant cases. Solid and invasive mucinous ADC cases showed low positivity for TTF-1 (84% and 40%, respectively) and Napsin A (88% and 80%, respectively), and invasive mucinous ADC cases showed high positivity for CK5/6 (80%). The sensitivity and specificity of TTF-1+Napsin A for ADC were 91% and 83%, respectively, whereas those of CK5/6+p40 for SCC cases were 90% and 96%, respectively. Discrepant cases of ADC are associated with solid and invasive mucinous subtypes and shorter survival.

Ovarian Cancer with TTF-1-positive Giant Pleural Dissemination.

Thyroid transcription factor 1 (TTF-1) is primarily expressed in lung and thyroid cancers, but it has also been observed in other cancers. A 60-year-old woman presented with worsening dyspnea, pleural effusion, lung metastases, a right ovarian tumor, and para-aortic intra-abdominal lymph node metastasis. Biopsies from the pleural dissemination revealed TTF-1-positive adenocarcinomas. To confirm the presence of the primary organ, biopsies were performed on a para-aortic intra-abdominal lymph node that ascended from the ovaries. An adenocarcinoma positive for TTF-1 was identified, thus confirming the diagnosis of ovarian cancer. Our findings revealed that TTF-1 positivity does not always signify a lung cancer origin.

Thyroid transcription factor‐1 expression in lung neuroendocrine tumours: a gender-related biomarker?

PurposeThyroid transcription factor‐1 (TTF‐1) assessed by immunohistochemistry (IHC) is a specific biomarker for lung adenocarcinoma, and is commonly used to confirm the pulmonary origin of neuroendocrine tumours (NET). The majority of the available data suggest that TTF-1 is favourable prognostic biomarker for lung adenocarcinomas, whereas its role is more conflicting for lung NET. The main aim of this multicenter retrospective study was to investigate the potentially relevant associations between TTF-1 biomarker and clinical and pathological features of the study population, as well as determine TTF-1 prognostic effect on the clinical outcome of the patients.MethodsA multicentre retrospective study was conducted on 155 surgically-removed lung NET, with available IHC TTF-1 assessment.ResultsMedian age was 59.5 years (range 13–86), 97 patients (62.6%) were females, 31 cases (20%) were atypical carcinoids, 4 (2.6%) had TNM stage IV. Mitotic count ≥2 per 10 high-power field was found in 35 (22.6%) subjects, whereas necrosis was detected in 20 patients (12.9%). TTF-1 was positive in 78 cases (50.3%). The median overall survival was 46.9 months (range 0.6–323) and the median progression-free survival was 39.1 months (range 0.6–323). Statistically significant associations were found between (1) TTF-1 positivity and female sex (p = 0.007); and among (2) TTF-1 positivity and the absence of necrosis (p = 0.018).ConclusionsThis study highlights that TTF-1 positivity differs according to sex in lung NET, with a more common TTF-1 positive staining in female. Moreover, TTF-1 positivity correlated with the absence of necrosis. These data suggest that TTF-1 could potentially represent a gender-related biomarker for lung NET.

Thyroid transcription factor 1 (TTF-1) negativity as a predictor of unfavorable response to EGFR-TKI therapy in advanced lung adenocarcinoma patients with EGFR mutations.

The absence of thyroid transcription factor 1 (TTF-1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF-1 expression on the clinical response to EGFR-tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD. The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed. A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF-1-negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF-1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF-1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF-1. Patients lacking TTF-1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression-free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR-TKIs compared to the TTF-1-positive patients with EGFR mutations. Patients with TTF-1-negative and EGFR-mutant LUAD show a diminished response to EGFR-TKIs.

The role of thyroid transcription factor-1 in differentiating lung adenocarcinomas from non-pulmonary adenocarcinoma effusions.

Effusions, characterized by abnormal fluid accumulations in body cavities, present difficulties in identifying the primary organs of metastatic tumors through cytopathologic investigation, particularly in cancer-related complications. This retrospective cross-sectional laboratory study aimed to investigate the role of thyroid transcription factor-1 (TTF-1) in distinguishing lung adenocarcinomas from non-pulmonary adenocarcinomas in effusions. The study was conducted at Almobarak Cytopathology Laboratory, a private cytopathology laboratory. H&E was used to confirm the histological diagnosis of 58 archived cell blocks. TTF-1 immunostaining patterns were then correlated with the histological diagnosis. Statistical analysis, including numerical and graphical data summaries, was conducted using the Chi-square test in SPSS 23. TTF-1 expression was observed in 20 (34.4%) cases, while 38 (65.5%) cases showed no TTF-1 reaction. Positive TTF-1 was found in pleural fluid in 61.1 % of lung adenocarcinomas, while negative TTF-1 was found in only 3.4%. TTF-1 was not detected in the majority of peritoneal fluid samples. There was a highly significant relationship between pleural fluid, TTF-1, and lung adenocarcinoma (p=0.000). The data provided further evidence that TTF-1 is a useful marker for distinguishing pulmonary adenocarcinomas from non-pulmonary adenocarcinoma tumors.

The relationship between thyroid transcription factor-1 positivity and epidermal growth factor receptor mutation in lung adenocarcinoma and its prognostic significance

The relationship between thyroid transcription factor-1 positivity and epidermal growth factor receptor mutation in lung adenocarcinoma and its prognostic significance

Prostate Adenocarcinoma With Atypical Immunohistochemistry Presenting With a Cheerio Sign

The most common cancer in men is prostate cancer. The Cheerio sign is the computed tomography finding of multiple pulmonary nodules with central lucency resembling the ring-shaped Cheerio breakfast cereal. Unlike bone metastasis, pulmonary involvement is less common. The Cheerio sign has malignant and benign etiologies. Thyroid transcription factor-1 (TTF-1) stain is commonly used in the diagnosis of primary lung cancer. TTF-1 positivity in cancers of prostate origin is rare, with only case reports and small case series available in the literature. Metastatic prostate cancer presenting with a Cheerio sign has not been reported in the literature.

Immunofluorescent and molecular characterization of effusion tumor cells reveal cancer site-of-origin and disease-driving mutations.

Effective cancer treatment relies on precision diagnostics. In cytology, an accurate diagnosis facilitates the determination of proper therapeutics for patients with cancer. Previously, the authors developed a multiplexed immunofluorescent panel to detect epithelial malignancies from pleural effusion specimens. Their assay reliably distinguished effusion tumor cells (ETCs) from nonmalignant cells; however, it lacked the capacity to reveal specific cancer origin information. Furthermore, DNA profiling of ETCs revealed some, but not all, cancer-driver mutations. The authors developed a new multiplex immunofluorescent panel that detected both malignancy and pulmonary origin by incorporating the thyroid transcription factor-1 (TTF-1) biomarker. Evaluation for TTF-1-positive ETCs (T-ETCs) was performed on 12 patient samples. T-ETCs and parallel ETCs from selected patients were collected and subjected to DNA profiling to identify pathogenic mutations. All samples were obtained with Institutional Review Board approval. Malignancy was detected in all samples. T-ETCs were identified in 9 of 10 patients who had clinically reported TTF-1 positivity (90% sensitivity and 100% specificity). Furthermore, DNA profiling of as few as five T-ETCs identified pathogenic mutations with equal or greater sensitivity compared with profiling of ETCs, both of which showed high concordance with clinical findings. The findings suggest that the immunofluorescent and molecular characterization of tumor cells from pleural effusion specimens can provide reliable diagnostic information, even with very few cells. The integration of site-specific biomarkers like TTF-1 into ETC analysis may facilitate better refined diagnosis and improve patient care.

Gastrointestinal Tract Duplications in Children: A Tertiary Referral Center Experience.

Objective:Gastrointestinal duplications are rare congenital anomalies. Herein, we present a single institutional experience in pediatric gastrointestinal tract duplications.Methods:Patient records from 2014 to 2019 were retrospectively evaluated for demographic data, clinical presentation, diagnostic methods, surgical findings, and pathological reports.Results:This study included 19 patients, of whom 10 were males and nine were females, with a median age of 30 (21 days-15.5 years) months. Three patients were antenatally and three were incidentally diagnosed. Abdominal pain, vomiting, constipation, and perianal accessory orifice were the most common presenting symptoms. Preoperative diagnostic workup included ultrasonography (n=13), cross-sectional imaging (n=8), and nuclear scintigraphy (n=1). A preoperative diagnosis was possible in 14 (74%) patients. The duplications originated from the foregut in seven (37%) patients, midgut in seven (37%), and hindgut in five (26%). Cystic duplications were observed in 14 (74%) patients and tubular in five (26%). The total surgical excision with (n=8) or without (n=10) associated organ resection was possible in 18 patients. Partial cyst excision with a complete mucosal removal was done in 1 patient. Heterotopic mucosa was present in six (32%) specimens. The respiratory origin with thyroid transcription factor-1 positivity was contained in two para-esophageal duplications. Among five patients with heterotopic gastric mucosa, 1 had presented with perforation and the others with hemorrhage.Conclusions:Duplications may involve any gastrointestinal segment. The clinical presentation is highly variable because of the wide variation in the involved segment and sizes and the possibility of bearing heterotopic mucosa. The surgery aims to totally excise the cyst or at least totally remove the inner mucosal lining.

P60.04 TTF1 Expression in Advanced Lung Adenocarcinoma and Survival Outcome: An Observational Study

Prognosis of advanced lung adenocarcinoma remains poor despite significant advances in treatment options. Current literature calls for independent prognostic biomarkers to better stratify patient risk. Thyroid transcription factor 1 (TTF1) is regulatory protein that is suggested to be a favourable prognostic indicator independent of stage at diagnosis. The mechanism for this remains unclear with loss of differentiation of tumour a possible explanation. Further research, however, is needed for clinical application. This study explores TTF1 expression in adenocarcinoma of the lung and its correlation to survival outcomes as well as explores patterns of incidence in relation to tumour grade, gain of function mutations and PD-L1 status. This is a retrospective, observational, single-centre study of lung adenocarcinoma diagnosed between July 2017 and July 2020 in a large regional cancer centre in Victoria, Australia. Immunohistochemical reports and patient specific data were collected from patient records and analysed with simple descriptive statistics, binomial testing and Kaplan-Meier survival curves. A total of 86 adenocarcinoma of lung primary cases were identified (Age Range 49-89, Mean 69, ratio female to male 56%:44%). Of the total cases, 83% were TTF1 positive (n=71) and 13% negative (n=10). Gain of function mutations were present in 10.5% (n=9) of the cohort, with majority of these cases being TTF1 positive (78%, n=7). PD-L1 status analysis was completed in 44.7% of cases, with a majority being TTF1 positive (80% n=20). Overall, TTF1 negative tumours appeared more likely to be poorly differentiated (p=0.02), however TTF1 positive tumours did not have a significant association with well differentiated tumours (p=0.56). Overall, TTF1 positive tumours had a significantly longer survival compared to TTF1 negative tumours (median survival 64.7 weeks vs 9.4 weeks, on univariate analysis p<0.0004) . TTF1 positive tumours seem to have a longer overall survival regardless of their PD-L1 status, compared to the TTF1 negative group (p=0.04). TTF-1 expression in lung adenocarcinoma appears to be a good prognostic indicator regardless of PD-L1 status. Whilst TTF-1 negative status appears to be correlated with poorly differentiated tumours, positive TTF1 status does not necessarily reflect a degree of differentiation. These findings, are hypothesis generating and being planned to be validated in a larger cohort in a prospective manner, to define the clinical utility of TTF1 as a predictive/prognostic biomarker.

Posterior pituitary tumours: patient outcomes and determinants of disease recurrence or persistence.

ObjectivePosterior pituitary tumours (PPTs) are rare neoplasms with the four recognised subtypes unified by thyroid transcription factor -1 (TTF-1) expression, according to the 2017 WHO classification. Though traditionally defined as low-grade neoplasms, a substantial proportion of them show recurrence/persistence following surgery.MethodsWe selected patients with PPTs in our cohort of 1760 patients operated for pituitary tumours over the past 10 years (2010–2019). The clinical, radiological, hormonal, histopathological profiles and long-term outcomes of the three cases identified (two pituicytomas and one spindle cell oncocytoma, SCO) were analysed. Following a literature review, data of all published cases with documented TTF-1 positive pituicytomas and SCOs were analysed to determine the predictors of recurrence/persistence in these tumours.ResultsPatients presented with compressive features or hypogonadism. Two had sellar-suprasellar masses. One had a purely suprasellar mass with a pre-operative radiological suspicion of pituicytoma. Two were operated by transsphenoidal surgery and one transcranially guided by neuronavigation. Histopathology confirmed spindle cells in a storiform arrangement and low Ki67 index. Immunohistochemistry showed positive TTF-1, S-100 expression and variable positivity for EMA, vimentin and GFAP. Re-evaluation showed recurrence/persistence in two patients. A literature review of recurrent/persistent pituicytoma (n = 17) and SCO (n = 9) cases revealed clinical clues (headache for pituicytomas, male gender for SCO), baseline tumour size (≥20.5 mm with sensitivity exceeding 80%) and longer follow-up duration as determinants of recurrence/persistence.ConclusionPPTs are rare sellar masses with quintessential TTF-1 positivity. Recurrent/persistent disease following surgery is determined by greater tumour size at baseline and duration of follow-up. This warrants intensive and long-term surveillance in these patients.

P22.04 Lung Metastasis of Thyroid Transcription Factor 1 Positive Endometrioid Carcinoma; A Case Report

Thyroid transcription factor 1 (TTF-1) is a protein which regulates transcription of genes specific for thyroid, lung, and diencephalon, and is used in anatomic pathology as a marker to determine if a tumor arises from lung or thyroid. TTF-1 positive rate in endometrial carcinoma (Grade 1-2) is as rare as 2%. We present a solitary pulmonary metastasis case from TTF-1 positive endometrioid carcinoma. A 84-year-old woman was addressed to our institution for an abnormal shadow in the chest. Chest CT showed 14mm nodule in the right lower lobe. She had a previous history of surgically resected endometrioid carcinoma (Grade 2) of the uterine corpus. Video assisted thoracic surgery was performed for diagnostic and therapeutic purposes. Intra-operative diagnosis was suspected lung metastasis of endometrioid carcinoma. Immunohistochemical staining revealed positive estrogen receptor, TTF-1 and PAX8. Based on the results, we made a diagnosis of metastatic endometrioid carcinoma. The postoperative course was uneventful. TTF-1 positive endometrioid carcinoma is rare. Medical history and immunohistochemistry are useful for differentiating from primary lung cancer. TTF-1 positive endometrioid carcinomas have reported a poor prognosis and require careful follow-up.

Difficulties in diagnostics of lung tumours in biopsies: an interpathologist concordance study evaluating the international diagnostic guidelines

AimsAccurate and reliable diagnosis is essential for lung cancer treatment. The study aim was to investigate interpathologist diagnostic concordance for pulmonary tumours according to WHO diagnostic criteria.MethodsFifty-two unselected lung and...

Aberrant thyroid transcription factor-1 expression in ovarian and nasopharyngeal carcinoma: Case reports with review of literature

Introduction: Thyroid transcription factor-1 (TTF-1) is the recommended and sensitive immunohistochemical (IHC) marker for diagnosing lung adenocarcinomas and thyroid neoplasms, at the primary as well as the metastatic site, and is useful to rule out these sites in cases with adenocarcinomas of unknown primary. However, aberrant nuclear TTF-1 expression has also been reported in malignancies arising from gastrointestinal tract (GIT), breast carcinoma, female genital tract (FGT), and colon. Here, we present our experience of aberrant expression of TTF-1 in ovarian and nasopharyngeal carcinoma (NPC). Materials and Methods: TTF-1 immunostain was performed on 16 cases of NPC using clones SP141 and 8G7G3/1. A case of ovarian serous carcinoma with aberrant TTF-1 expression has also been discussed. Results: Of 16 cases of NPC, 2 cases (12.5%) showed strong TTF-1 expression with clone SP141, while all were negative with 8G7G3/1. In one of the case initial diagnosis of metastatic lung adenocarcinoma was made on cervical node biopsy as the tumor was negative for p40 and showed strong nuclear positivity for TTF-1 (SP141 clone). However, on clinical suspicion of NPC Epstein-Barr virus-encoded small RNA (EBER) by in situ hybridization was performed which was positive, and repeat TTF-1 using clone 8G7G3/1 was negative, suggested a NPC. In the case of ovarian tumor, cells were strongly positive for CK7 and TTF-1 (SP141 clone) expression, and thus the tumor was erroneously diagnosed as metastatic adenocarcinoma from a primary lung. However, IHC in the resected specimen showed strong expression for PAX-8 and TTF-1 using SP141 clone, while negative with clone 8G7G3/1 clone (Ventana), leading to final diagnosis of high-grade serous carcinoma of ovary with aberrant TTF-1 expression. In this case, addition of PAX-8 in initial biopsy diagnosis would have saved from labeling it as primary from lung. Conclusion: The sensitivity and aberrant expression vary between the various antibody clones used, with increased expression seen by SP141 clone as compared to 8G7G3/1 in our cases. Our findings highlight the significance of using a panel of diagnostic IHC markers before final diagnosis and importance of clinical details.

Value of TTF-1 expression in non-squamous non-small-cell lung cancer for assessing docetaxel monotherapy after chemotherapy failure.

Docetaxel is one of the standard second/third-line treatments for non-small-cell lung cancer (NSCLC) following a failed response to prior cytotoxic chemotherapy. The predictive biomarker for the effectiveness of docetaxel therapy remains undetermined. However, thyroid transcription factor-1 (TTF-1) is known to be a good prognostic factor for a variety of chemotherapies. To investigate the association between TTF-1 expression and docetaxel monotherapy outcome, 82 patients with non-squamous NSCLC who received second/third-line docetaxel monotherapy were retrospectively screened. All backgrounds were well-balanced whether or not tumor TTF-1 was expressed, and the present clinical outcomes were similar to those reported by previous clinical studies. A better clinical outcome was indicated in TTF-1 positive compared with TTF-1 negative patients, with disease control rates of 69% vs. 42%, respectively (P=0.03) and median overall survival of 393 days vs. 221.5 days, respectively (P<0.01). Furthermore, progression free survival tended to be longer in TTF-1 positive compared with TTF-1 negative patients (median, 100 days vs. 67 days; P=0.09). Multivariate analysis revealed that TTF-1 positivity was a unique significant predictor for assessing overall survival after docetaxel monotherapy. TTF-1 positivity may be useful for predicting survival outcome in patients who received docetaxel monotherapy after failure of prior chemotherapy.

Morphometric and immunohistochemical features of TTF-1 positive lung tumors: improvement of approaches to the diagnosis of unknown primary sites metastases

Verification of lung tumors in the practical activity of a pathomorphologist reached a completely different level due to the use of additional highly sensitive diagnostic methods (immunohistochemical (IHC) and cytogenetic studies). Thyroid transcription factor 1 (TTF-1) plays a key role in lung morphogenesis and is expressed in about 90 % of pulmonary small cell carcinomas. The positivity of TTF-1 in pulmonary and extrapulmonary neuroendocrine tumors is actively debated in the literature, therefore, the results of IHС on TTF-1 in metastases from an unknown source should be interpreted carefully and constantly improve differential diagnostic algorithms, expanding IHC panels with organ-specific markers, and focus on additional morphometric indicators research of nuclei of tumor cells.The aim of the work is to investigate the complex of morphological, morphometric, and IHC characteristics of TTF-1 positive lung tumors to improve the diagnostic algorithms for metastases from an unknown primary source.Materials and methods. A retrospective analysis of histological, morphometric and IHC characteristics of the biopsy material TTF-1 of positive lung carcinomas from 36 patients (10 women and 26 men) aged 29 to 81 years (mean 58.03±10.83 years) for the period 2015–2018, taken from the archive of the morphological department of the medical-diagnostic center of LLC “Pharmacies of the Medical Academy” (Ukraine, Dnipro).Results. In the diagnosis of carcinomas of unknown primary localization with suspected lung origin, it is necessary to take into account morphological, morphometric and IHC features together, which is associated with the similarity of metastases of squamous cell carcinomas of the head and neck, mucinous adenocarcinomas of the gastrointestinal tract and neuroendocrine carcinomas from Merkel cells corresponding to the histological forms lung tumors, as well as insufficient sensitivity of the marker TTF-1.Conclusions. Use of the minimum primary (Cytokeratin, Pan AE1 / AE3 (+) / Vimentin (- / +) / CD45 (-) / S100 (- / +)) and secondary (Ck 7 +, Ck 20 -, TTF-1 + ) IHC panels will prove that the phenotype of carcinoma of unknown primary site corresponds to the form of disseminated lung carcinoma, and additional markers Сk HMW, p63, Chromogranin A, Synaptofisin and / or CD56 together with morphometric indices of the nuclei will determine the histological form of lung carcinoma with justification for the use of appropriate therapy