TTF-1 Expression Research Articles

Spindle Cells Oncocytoma and Rathke’s Cyst; A Collision Sellar Tumor– Brief Communication & Case Report

Collision tumors comprising of pituitary adenomas with other sellar neoplasms are rare. Histological examination is necessary since preoperative studies cannot guarantee an accurate diagnosis. A 66-year-old man with headache and progressive visual alterations, MRI showed a sellar tumor that was diagnosed as pituitary adenoma and graduated as HV IIIc. He underwent surgery and two lesions were resected, one on the cavernous sinus and the other one in sellar region. The lesion of the venous sinus corresponds to a cyst covered by a ciliated pseudostratified epithelium that was diagnosed as Rathke's cyst, and the second one was formed by a neoplastic lesion of elongated cells with focal cellular atypia in a sarcomatous pattern, forming fascicles alternating with a pattern formed by medium eosinophilic cells predominantly in elongated cells in a stroma with abundant sinusoids. For immunohistochemistry, the epithelium of the cyst was PTTG-1, cytokeratin 6/8, and chromogranin positive, while the other lesion was positive chromogranin, FSH, LH PTTG-1, TTF-1, while the spindle cells area was positive immunoreaction for PTTG-1, GFAP, S-100, and VIM and weak expression for TTF-1. These histologic and immunohistochemical findings are suggestive of spindle cells oncocytoma and Rathke cyst, is a rare sellar collision tumor. The expression of TTF-1 in the spindle cell oncocytoma with the idea of common histogenesis for pituicytoma and SCOs and raise the possibility of more aggressive growth in SCOs as compared to pituicytoma.

TTF1 suppresses neuroblastoma growth and induces neuroblastoma differentiation by targeting TrkA and the miR-204/TrkB axis

SummaryNeuroblastoma (NB) is the most common extracranial malignant solid tumor in children. We found that TTF1, TrkA, and miR-204 were lowly expressed, whereas TrkB was highly expressed in undifferentiated NB tissues. Meanwhile, TTF1 expression correlated positively with TrkA and miR-204 expression but negatively with TrkB expression. The TTF1 promoter was hypermethylated in undifferentiated NB tissues and SK-N-BE cells, leading to TTF1 downregulation. We also identified miR-204, which directly targets TrkB, as a transcriptional target of TTF1. Functionally, TTF1 suppressed proliferation, migration, and invasion of NB cells, whereas induced cell cycle arrest, apoptosis, and autophagy of NB cells by regulating TrkA and the miR-204-TrkB axis. Furthermore, TTF1 suppressed tumor growth and promoted neurogenic differentiation in a NB xenograft mouse model. Our study demonstrates that TTF1 reduces tumor growth and induces neurogenic differentiation in NB by directly targeting TrkA and the miR-204/TrkB axis.

Abstract 5200: The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI)

Abstract Background: HPD is an unexpected rapid acceleration of tumor growth reported for patients treated with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinical and genetic risk factors. Method: A total of 203 patients with NSCLC who received ICI at Northwestern Memorial Hospital during 2008-2020 were included. Tumor growth kinetics (TGK) on immunotherapy and TGK pre-immunotherapy were collected and TGK ratio (TGKR) was calculated. HPD was defined as TGKR≥2. Result: HPD was observed in 16% (n=33) of patients. HPD was significantly associated with high ECOG (3-4 vs 1-2) [OR = 4.52, 95% CI = 1.31 to 16.29, P = 0.01], presence of bone metastasis [OR = 2.51, 95% CI = 1.10 to 5.28, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, 95% CI = 1.24 to 5.81 P = 0.01], thrombocytosis (platelet count >450k) [OR = 5.31, 95% CI = 2.07 to 14.70, P=0.0003], and treatment with PD-L1 inhibitor vs PD-1 inhibitor [OR = 2.14, 95% CI= 0.97 to 4.68, P= 0.068]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, 95% CI = 0.13 to 0.86, P = 0.01], ICI combined with chemotherapy vs ICI monotherapy [OR = 0.24, 95% CI = 0.055 to 0.97, P=0.04], and positive TTF-1 expression [OR = 0.46, 95% CI = 0.21 to 1.02, P=0.057]. HPD was not associated with histology of NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and large cell neuroendocrine carcinoma), age(<70, ≥70), sex, smoking history, number of metastatic lesions (<3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, and TNM staging. Conclusion: The incidence of HPD in NSCLC treated with ICI was consistent with current literature. High NLR and platelet count are suggestive of an immunosuppressive environment that could contribute to the rapid growth of tumors. To our knowledge, this is the first study to report an inverse correlation of PD-L1 expression and TTF-1 expression with HPD. The strength of our study lies in a large number of patients. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted. Citation Format: Hyeonseon Kim, Yeun Ho Lee, Chiwoo Song, Leeseul Kim, Min Jeong Kim, Horyun Choi, Jinah Kim, Young Kwang Chae. The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5200.

PSC subtyping based on TTF-1 and p40 expression reveals distinct molecular characteristics and therapeutic strategies.

Pulmonary sarcomatoid carcinoma (PSC) is a unique form of poorly differentiated nonsmall cell lung cancer (NSCLC) and is notorious for its highly malignant nature and dismal prognosis. To introduce effective treatment for PSC patients, precise subtyping of PSC is demanding. In our study, TTF-1 and P40 immunohistochemistry (IHC) staining were applied to 56 PSC patients with multiomics data. According to IHC results, we categorized these patients into three subgroups and profiled their molecular contexture using bioinformatic skills. IHC results classified these patients into three subgroups: TTF-1 positive subgroup (n=27), P40 positive subgroup (n=15) and double-negative subgroup (n=14). Spindle cell samples accounted for 35.71% (5/14) of double-negative patients, higher than others (P=.034). The three subgroups were heterogeneous in the genomic alteration spectrum, showing significant differences in the RTK/RAS pathway (P=.004) and the cell cycle pathway (P=.030). The methylation profile of the double-negative subgroup was between the other two subgroups. In similarity analysis, the TTF-1 and p40 subgroups were closely related to LUAD and LUSC, respectively. The TTF-1 positive subgroup had the highest leukocyte fraction (LF) among several cancer types, and the tumor mutation burden (TMB) of the p40 positive subgroup ranked third in the TMB list, suggesting the applicability of immunotherapy for PSC. The study established a new subtyping method of PSC based on IHC results and reveals three subgroups with distinct molecular features, providing evidence for refined stratification in the treatment of PSC.

The incidence and predictive factors of hyperprogressive disease (HPD) in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI).

e21025 Background: HPD is an unexpected and rapid acceleration of tumor growth in patients following treatment with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinicopathological and genetic predictive factors. Methods: A total of 203 patients with NSCLC treated with ICI at Northwestern Memorial Hospital during 2015-2020 were included. Clinicopathological data were retrospectively gathered and analyzed. Tumor growth kinetics (TGK) of pre-immunotherapy and post-immunotherapy were collected and TGK ratio (TGKr) was calculated. HPD was defined as TGKr≥2. Results: HPD was observed in 16% (33/203) of patients. There was a statistically significant difference in overall survival(OS) between the two groups (non-HPD vs. HPD) [OR = 2.39, P < 0.01]. The progression-free survival(PFS) also showed a statistically significant difference in patients (non-HPD vs HPD) [OR = 3.4, P < 0.01]. The median OS and PFS of patients with HPD were 13.57 months and 2.2 months respectively. The median OS and PFS of patients without HPD were 30.67 months and 7.3 months respectively. HPD was significantly associated with performance status (3-4 vs. 1-2) [OR = 4.52, P = 0.01], presence of bone metastasis [OR = 2.51, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, P = 0.01], thrombocytosis (platelet count > 450k) [OR = 5.31, P < 0.01], and treatment with PD-L1 inhibitor vs. PD-1 inhibitor [OR = 2.14, P = 0.06]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, P = 0.01], ICI combined with chemotherapy vs. ICI monotherapy [OR = 0.24, P = 0.04], and positive TTF-1 expression [OR = 0.46, P = 0.06]. HPD was not associated with histological subtypes of NSCLC, age(< 70, ≥70), sex, smoking history, number of metastatic lesions (< 3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, TNM staging, tumor mutational burden (TMB) (< 10, ≥10), microsatellite stability index (MSI), human leukocyte antigen-1 (HLA-1) heterozygosity, hemoglobin(≤12, > 12), albumin(≤3.5, > 3.5), and LDH(≤240, > 240). Conclusions: The incidence of HPD, 16%, was consistent with current literature. NLR ≥5, platelet count > 450k, poor performance status, presence of bone metastasis, treatment with PD-L1 inhibitor, negative PD-L1 expression, negative TTF-1 expression, and ICI monotherapy were predictors of HPD. To our knowledge, this is the first study to report an inverse correlation of TTF-1 expression, and non correlation of HLA-1 heterozygosity with HPD. The strength of our study is that we analyzed recently emerging next-generation sequencing (NGS) data to find novel predictors of HPD. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted.

Mesonephric-like Endometrial Carcinoma: Results From Immunohistochemical Screening of 300 Endometrial Carcinomas and Carcinosarcomas for This Often Overlooked and Potentially Aggressive Entity.

Mesonephric-like endometrial carcinoma is a rare but frequently misclassified and aggressive malignancy. KRAS mutations, limited estrogen receptor (ER) expression, and TTF-1, GATA3, and luminal CD10 expression are described in these tumors, but an immunohistochemistry-based screening approach has not been studied. We assessed 300 endometrial carcinomas/carcinosarcomas to ascertain the specificity of TTF-1/GATA3/luminal CD10 expression with or without ER staining for this diagnosis. Next-generation sequencing and morphologic review were performed on screen-positive cases. In all, 3% (9/300) were TTF-1+; 2 coexpressed GATA3. No cases expressed luminal CD10 or GATA3 in isolation. Two TTF-1+/ER- cases, one of which was also GATA3+, were reclassified as mesonephric-like based on morphology and molecular results (KRAS mutations without mismatch repair deficiency, TP53 mutations, or PTEN mutations): these represented 0.7% of all cases (2/300). The reclassified cases were originally diagnosed as grade 1 and 2 endometrioid carcinoma, and the latter had pulmonary metastases and pelvic recurrences. Six TTF-1+ cases retained their original serous (3) and endometrioid (3) diagnoses; 1 was reclassified as dedifferentiated. All had negative or low ER. KRAS mutations were identified in 4 TTF-1+ non-mesonephric-like cases, including 1 serous and 1 grade 3 endometrioid with p53 abnormalities, 1 mismatch repair-deficient endometrioid with a complex molecular profile, and 1 endometrioid with mucinous differentiation. These findings suggest that TTF-1 and ER are good first-line screens for mesonephric-like carcinoma, but caution that a TTF-1+/ER- immunoprofile is not specific, even in the setting of KRAS mutations. A final diagnosis of mesonephric-like carcinoma requires integration of morphologic and immunohistochemical features, with molecular support when relevant.

Thyroid Carcinoma with NSD3::NUTM1 Fusion: a Case with Thyrocyte Differentiation and Colloid Production

In this report, we present a high-grade thyroid carcinoma with an NSD3::NUTM1 fusion detected on expanded next-generation sequencing testing. Nuclear protein of the testis (NUT) carcinomas comprise high-grade, aggressive tumors characterized by rearrangements of the NUTM1 gene with various partner genes, most commonly the bromodomain protein genes BRD4 and BRD3. Approximately 10% of NUT carcinomas contain an NSD3::NUTM1 fusion. NUT carcinomas manifest as poorly differentiated or undifferentiated squamous carcinomas, and 33% show areas of mature squamous differentiation. Only exceptionally have NUT carcinomas shown histology discordant from poorly differentiated/undifferentiated squamous carcinoma, and a thyroid NUT carcinoma with histologic thyrocyte differentiation has not been described to date. Our patient’s tumor exhibited mixed cytologic features suggestive of squamoid cells or papillary thyroid carcinoma cells. Overt squamous differentiation was absent, and the tumor produced colloid in poorly formed follicles. Immunophenotypically, the carcinoma was consistent with thyrocyte differentiation with expression of monoclonal PAX8, TTF1, and thyroglobulin (the last predominantly in extracellular colloid). There was zero to < 2% reactivity for proteins typically diffusely expressed in NUT carcinoma: p40, p63, and cytokeratins 5/6. NUT protein expression was equivocal, but fluorescence in situ hybridization confirmed a NUTM1 rearrangement. This exceptional case suggests that NUTM1 fusions may occur in an unknown number of aggressive thyroid carcinomas, possibly with distinctive histologic features but with thyrocyte differentiation. Recognition of this entity potentially has significant prognostic implications. Moreover, thyroid carcinomas with NUTM1 fusions may be amenable to treatment with NUT carcinoma-targeted therapy such as a bromodomain and extraterminal domain protein small molecular inhibitor (BETi).

Retrospective Data Analysis of Patients With Metastatic Lung Adenocarcinoma With or Without KRAS-Mutation or TTF1-Expression.

Patients with lung adenocarcinoma not expressing TTF1 and those with a KRAS mutation have worse prognosis. However, available data are limited and sometimes contradictory. Therefore, this retrospective cohort analysis aimed to clarify whether there was a difference in overall survival and progression-free survival between these groups of patients. In total, data derived from 181 patients with metastatic lung adenocarcinoma treated at the Martha-Maria Halle-Dölau Hospital from 2016 to 2019 were analyzed. Kaplan-Meier curves were generated, and associated values, such as median survival and its confidence intervals, were determined using the log-rank test. A benefit in overall survival (OS) (8.4 vs 5.8 months; HR, .8; 95% CI, .53-1.19; P = .267) was associated with positive TTF1 expression, but this was not statistically significant. The same trend was shown with the progressive free survival (PFS) (6.5 vs 4.6 months; HR, .76; 95% CI, .51-1.20; P = .162). In patients with a KRAS mutation, there was no difference in OS compared to those with a wildtype KRAS. The median survival was almost identical at 7.5 months (KRAS mutation, 95% CI, 3.32-11.74) and 7.0 months (KRAS wildtype, 95% CI, 3.59-10.41). Additionally, in PFS, there was no difference between the 2 groups (5.8 vs 6.3months). Our analysis did not show a worse prognosis in patients with a KRAS mutation or in those with missing TTF1 expression, which is most likely related to the new therapeutic options. As a result of the administration of immunotherapy in patients with a KRAS mutation and the change from a regimen containing pemetrexed to a regimen containing no pemetrexed, the corresponding patients no longer seem to have a worse prognosis.

Introduction and expression of PIK3CAE545K in a papillary thyroid cancer BRAFV600E cell line leads to a dedifferentiated aggressive phenotype

Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, which exhibits rapid progression and is almost universally fatal. At least a subset of ATC is thought to arise from pre-existing well-differentiated thyroid cancer, most frequently papillary thyroid cancer (PTC). While PIK3CA mutations are rare in PTC, they are common in ATC and tend to co-occur with BRAF mutations. This provided the rationale for our study to identify the potential role of PIK3CA mutations in the progression from well-differentiated to undifferentiated thyroid cancer. We introduced PIK3CAE545K into the LAM1 PTC cell line, which carries a BRAFV600E mutation. In culture, the engineered cell line (LAM1:PIK3CAE545K) proliferated faster and demonstrated increased clonogenic potential relative to the parental line carrying an empty vector (LAM1EV). Both the LAM1EV and LAM1:PIK3CAE545K edited lines were implanted into hind flanks of athymic nude mice for in vivo determination of disease progression. While tumour weights and volumes were not significantly higher in LAM1:PIK3CAE545K mice, there was a decrease in expression of thyroid differentiation markers TTF-1, thyroglobulin, PAX8 and B-catenin, suggesting that introduction of PIK3CAE545K led to dedifferentiation in vivo. Collectively, this study provides evidence of a role for PIK3CAE545K in driving disease progression from a well-differentiated to an undifferentiated thyroid cancer; however, over-expression was not a determinant of an accelerated growth phenotype in ATC.Graphical

Immunocytochemical Evaluation of TTF-1, Napsin-A, and p-63 for Subtyping of Non-Small Cell Lung Carcinoma and Clinicopathological Correlation.

Carcinoma of lung is the most common cause of cancer-associated mortality worldwide. About 70% of lung cancer cases are unresectable and present in advanced stages. So, cytology and small core needle biopsy specimen are available for diagnostic as well as prognostication workup. Subtyping of non-small cell lung cancer (NSCLC) is essential for the treatment and further workup study. For this, immunocytochemistry (ICC) plays a crucial role that helps in early diagnosis. Subtyping of NSCLC from cytology samples using ICC markers like TTF-1, Napsin-A, and p63 and their clinicopathological correlation are the aims of the study. This ambispective study was conducted in the pathology department of a tertiary care hospital of eastern India for a 2-year period from 2018 to 2020. In our study, 46 cytologically diagnosed cases of NSCLC were included. Subtyping was done by cytomorphology and correlated with ICC expression, histopathology, and clinicopathological parameters. In our study, adenocarcinoma (ADC) was the most common (32.61%) cancer. Most cases of ADC showed positive expression of TTF-1 and Napsin-A, and p63 was positive in most cases of squamous cell carcinoma (SCC). Concordance with cytomorphology and ICC was 87.50% and 81.81% with ADC and SCC, respectively. Cyto-ICC-histo concordance was observed in 85.51% of ADC and 66.66% of SCC cases. Sensitivity was 100%, 93.1%, and 100% for TTF-1, Napsin-A, and p63, respectively. Specificity of both TTF-1 and Napsin-A was 88.2% and for p63 was 93.8%. In small biopsy along with cytology samples, ICC is cost-effective and plays an important role in early diagnosis along with management of NSCLC.

Mesonephric-like Adenocarcinoma of the Uterine Corpus: Comprehensive Immunohistochemical Analyses Using Markers for Mesonephric, Endometrioid and Serous Tumors.

Mesonephric-like adenocarcinoma (MLA) of the uterine corpus is a rare but distinct malignant tumor of the female genital tract, demonstrating a characteristic morphology and unique immunohistochemical profiles and molecular alterations. We conducted immunohistochemical staining (IHC) to make precise differential diagnoses of uterine MLAs from common histological subtypes of endometrial carcinomas. We collected 25 uterine MLAs and performed IHC for GATA3, TTF1, CD10, ER, PR, p16, p53, and HER2. Seventeen cases (68.0%) showed at least moderate nuclear GATA3 immunoreactivity in ≥25% of tumor cells. Most cases expressed TTF1 (17/21, 81.0%) and CD10 (luminal; 17/21, 81.0%). Heterogeneous TTF1 expression was noted in 12 cases. An inverse pattern of GATA3 and TTF1 staining was observed in eight cases (32.0%). Three cases (12.0%) showed moderate-to-strong ER expression in ≥25% of tumor cells, and two cases (8.0%) showed moderate-to-strong PR expression in ≥5% of tumor cells. These hormone receptor-positive MLAs varied in intensity and proportion of GATA3 staining. None of the 25 cases exhibited either diffuse and strong p16 expression or aberrant p53 expression. Five cases (20.0%) showed equivocal HER2 immunoreactivity (score 2+), but HER2 FISH confirmed that none of them exhibited HER2 gene amplification. In summary, a small subset of uterine MLAs displayed atypical IHC results: focal but strong expression of ER or PR, the complete absence of GATA3 immunoreactivity, the concurrent expression of mesonephric and hormone receptors, and the inverse pattern of GATA3 and TTF1 staining. These unusual immunophenotypes may complicate the differential diagnosis of MLA. Moreover, pathologists should be encouraged to interpret the IHC results cautiously.

TTF-1 Immunoexpression in Primary Rectal Adenocarcinoma with Brain Metastasis

Abstract Introduction/Objective Rectal adenocarcinoma metastatic to the brain occurs in 0.6%-3% of cases and is associated with advanced-stage disease.TTF-1 expression in rectal adenocarcinoma is an uncommon finding and less than five cases of TTF-1 positive rectal adenocarcinomas have been reported in the literature. Herein, we report a primary rectal adenocarcinoma with biopsy-proven brain metastasis, radiographic evidence of hepatic and pulmonary involvement and unique expression of TTF-1, a marker with high sensitivity for primary pulmonary and thyroid lesions. Furthermore, we discuss the importance of distinguishing this entity from Pulmonary Enteric Adenocarcinoma (PEA). Methods/Case Report A 68-year-old male with hypertension presented with a two-day history of left facial drooping and dysarthria. Brain MRI revealed a 2.9 cm, contrast-enhancing, solitary, right insular mass. A pterional craniotomy and gross total resection of the lesion was performed. Microscopic examination revealed metastatic adenocarcinoma with immunohistochemical expression of CAM 5.2, CDX2, CK20, focal immunoreactivity with Napsin A and TTF-1, and lack of expression of CK7 and Synaptophysin. Radiographic investigation revealed a right posterior rectal lesion and multiple hepatic and bilateral pulmonary nodules. Sigmoidoscopy a fungating, partially circumferential, ulcerated, and friable rectal mass extending 6 cm proximally from the anal verge. Biopsy demonstrated invasive well- differentiated rectal adenocarcinoma with microsatellite stable phenotype, expression of CDX2, CD20, TTF-1 in the lesional cells, and lack of immunostaining with CK7. Given these findings, we favored a diagnosis of invasive well- differentiated rectal adenocarcinoma. Results (if a Case Study enter NA) N/A Conclusion TTF-1 positive rectal adenocarcinoma is an important differential diagnosis for PEA. As the two primary lesions share histomorphological features, clinical history, radiological findings and immunohistochemical staining with CK7 can aid in distinguishing between the two entities. Recent literature suggests a possible role for CDH17 and SATB2 immunostaining to increase the sensitivity and specificity of distinction between the two entities. Lack of expression of CK7 in both the rectal and brain lesion biopsies, radiological finding of numerous bilateral pulmonary infiltrates and one large, solitary rectal mass supports the diagnosis of advanced stage primary rectal adenocarcinoma with distal metastasis in our patient.

P56.04 Pathological Features & Prognosis of NSCLC Patients With Enteric Adenocarcinomas Without Expression of TTF-1 and Napsin A

Enteric differentiation can occur in lung adenocarcinoma, and when this component exceeds 50%, the tumor is classified as pulmonary adenocarcinoma with enteric differentiation (PAED). The enteric pattern of enteric lung adenocarcinoma shares morphologic and immunohistochemical features with colorectal adenocarcinoma and it consists of glandular and/or papillary structures sometimes with a cribriform pattern, lined by tumor cells that are mostly tall-columnar with nuclear pseudostratification, luminal necrosis, and prominent nuclear debris. Poorly differentiated tumors may have a more solid pattern. These tumors show at least one immunohistologic marker of enteric differentiation (CDX-2, CK20 or MUC2). Enteric adenocarcinoma is a rare histologic type of primary lung adenocarcinoma. Detailed clinical, pathological and molecular features about these subgroup of patients is lacking, particularly if TTF-1 and Napsin A aren't expressed. NSCLC patients who were diagnosed from January 2018 until March 2021 were identified by review of the patient records. Only lung adenocarcinoma patients whose tumors didn`t express either TTF-1 or Napsin A, but were positive for either CDX-2, CK20 or MUC2 were included in the data analysis. Primary tumor of the gastrointestinal tract was excluded either by PET-CT and/or CT and endoscopy (gastroscopy, colonoscopy, and rectoscopy). A total of fourteen (eight male (57,1%) and six female (42,9%) patients were identified in the patients` records. On average, the patients were 67 years old, the median age was 68. The youngest patient was 54 and the oldest one was 83 years old. Three patients were diagnosed at local stages (I-III), eleven patients had metastatic disease (stage IV). Four of these eleven patients had a mutation of the KRAS gene, which corresponds to 37%. This percentage is higher than the average frequency of mutations in the KRAS gene in pulmonary adenocarcinomas (25%). Half of the patients had a tumors with protein expression of PD-L1 (50%). Four patients of the complete cohort underwent surgical resection of the primary tumor and five patients received radiotherapy. Every patient, who got radiotherapy, suffered from stage IV. Three patients received irradiation of brain metastasis and two of bone metastasis. A systemic therapy was administered to nine patients. Seven patients had a combined chemo-/ immuntherapy as firstline treatment (either cisplatin, pemetrexed, and pembrolizumab or carboplatin, nab-paclitaxel, and atezolizumab) and one got only a combination chemotherapy (carboplatin and nab-paclitaxel). Median disease-free survival was eight, median progression-free survival was four months. Median overall survival could not be calculated. However, six and twelve months survival rates were 35.8 and 25.0 %, respectively. This is the far largest reported series of PAED patients without any expression of TTF1- or Napsin A. It seems that this subgroup of pulmonary adenocarcinoma patients has a poorer prognosis compared to other patients with lung adenocarcinomas.

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.

Thyroid Transcription Factor-1: Structure, Expression, Function and Its Relationship with Disease.

Thyroid transcription factor-1 (TTF-1/NKx2.1) is a member of the NKx2 tissue-specific transcription factor family, which is expressed in thyroid follicle, parathyroid gland, alveolar epithelium, and diencephalon which originated from ectoderm, and participates in the differentiation, development, and functional maintenance of the above organs. Recent studies have shown that the abnormal expression of TTF-1 is closely related to the occurrence of a variety of human diseases and can be used as a potential new target for the diagnosis and treatment of related diseases. In this article, in order to strengthen the systematic understanding of TTF-1 and promote the progress of related research, we reviewed the structure, expression regulation, biological functions of TTF-1, and its role in the occurrence and development of human-related clinical diseases. Meanwhile, we prospect the future research direction of TTF-1, which might ultimately contribute to the understanding of the pathogenesis of related clinical diseases and the development of new prevention and treatment strategies.

SMARCA4-Deficient Undifferentiated Tumor Diagnosed on Adrenal Sampling.

SMARCA4-deficient undifferentiated tumor has distinct clinicopathologic features. We describe our experience with primary diagnosis on adrenal sampling. We collected six SMARCA4-deficient undifferentiated tumors diagnosed on adrenal sampling. Immunostains for SMARCA4, SF-1, inhibin, calretinin, S-100 protein, EMA, and TTF-1 were performed. A control group of 63 primary adrenocortical tumors was also immunostained. Patients included four men and two women (aged 52-77 years). Five had unilateral adrenal masses and one bilateral (range, 2.4-9.6 cm). Five had pulmonary masses, and one had a midline mediastinal mass. All cases had a monotonous epithelioid appearance and variable rhabdoid morphology. Immunophenotypically, all six cases had loss of nuclear SMARCA4 expression and no staining for SF-1, inhibin, calretinin, or S-100 protein. Variable EMA immunoreactivity was present in four of six cases and focal nuclear TTF-1 expression in one of six. All 63 adrenocortical neoplasms had retained nuclear SMARCA4 expression. SMARCA4-deficient undifferentiated tumor may present in the adrenal gland, and this series likely represents metastases from thoracic primaries. Because of the frequent absence of lineage marker expression, knowledge of the characteristic clinical presentation, the rhabdoid morphology, and the typical immunophenotype (loss of SMARCA4/BRG1) allow for appropriate distinction from adrenocortical carcinoma.

Novel genetic characteristics in low-grade fetal adenocarcinoma of the lung.

BackgroundLow‐grade fetal adenocarcinoma of the lung (L‐FLAC) is a rare subtype of lung adenocarcinoma with undetermined histological features and genetic abnormalities. In this study, we attempted to investigate the pathological characteristics and genomic profiles of L‐FLAC.MethodsAmong 9839 cases of primary lung adenocarcinoma resected at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2011 and June 2016, three cases diagnosed with L‐FLAC were selected. An immunohistochemical profile and whole exome sequencing (WES) using tumor and normal tissues was conducted. The last follow‐up date of patients was January 2021.ResultsThree cases diagnosed with L‐FLAC were finally screened, suggesting a percentage of 0.03%. All three patients were male and diagnosed as stage I following radical lobectomy. The missense variant was found to be the major gene mutation type using WES. CTNNB1 and DICER1 were the two most frequent gene mutations. All cases demonstrated positive TTF‐1 expression. In addition, two patients showed positive expression of β‐catenin (nuclear/cytoplasmic expression), CgA and Sny. Negative expression of PD‐L1 in tumor cells was observed in all three cases. One case with a relatively high tumor mutation burden (TMB) (2.18 mut/Mb) had an inferior overall survival of 11.5 months. However, the other two cases with a lower TMB (0.12 and 0.74 mut/Mb) still acquired disease‐free status up to the last follow‐up date.ConclusionsL‐FLAC has a specific molecular background which is different from lung adenocarcinoma. Furthermore, gene heterogeneity was found and might be the reason for a dramatically different prognosis in these L‐FLAC patients.

Correlation of TTF-1 immunoexpression and EGFR mutation spectrum in non-small cell lung carcinoma.

BackgroundThyroid transcription factor (TTF-1) is a diagnostic marker expressed in 75%–85% of primary lung adenocarcinomas (ACs). Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene is the most common targetable driver alteration in lung AC. Previous studies have shown a positive correlation between TTF-1 and EGFR mutation status. We aimed to determine the predictive value of TTF-1 immunoexpression for underlying EGFR mutation status in a large Indian cohort. MethodsThis retrospective designed study was conducted with medical record data from 2011 to 2020. All cases of primary lung AC and non–small cell lung carcinoma not otherwise specified (NSCLC, NOS) with known TTF-1 expression diagnosed by immunohistochemistry using 8G7G3/1 antibodies and EGFR mutation status diagnosed by quantitative polymerase chain reaction were retrieved, reviewed, and theresults were analyzed. ResultsAmong 909 patient samples diagnosed as lung AC and NSCLC, NOS, TTF-1 was positive in 76.8% cases (698/909) and EGFR mutations were detected in 29.6% (269/909). A strong positive correlation was present between TTF-1 positivity and EGFR mutation status (odds ratio, 3.61; p < .001), with TTF-1 positivity showing high sensitivity (90%) and negative predictive value (87%) for EGFR mutation. TTF-1 immunoexpression did not show significant correlation with uncommon/dual EGFR mutations (odds ratio, 1.69; p = .098). EGFR–tyrosine kinase inhibitor therapy was significantly superior to chemotherapy among EGFR mutant cases irrespective of TTF-1 status; however, no significant differences among survival outcomes were observed. ConclusionsOur study confirms a strong positive correlation between TTF-1 expression and common EGFR mutations (exon 19 deletion and exon 21 L858R) in advanced lung AC with significantly high negative predictive value of TTF-1 for EGFR mutations.

Joint Detection of Tap and CEA Based on Deep Learning Medical Image Segmentation: Risk Prediction of Thyroid Cancer.

In recent years, the incidence of thyroid nodules has shown an increasing trend year by year and has become one of the important diseases that endanger human health. Ultrasound medical images based on deep learning are widely used in clinical diagnosis due to their cheapness, no radiation, and low cost. The use of image processing technology to accurately segment the nodule area provides important auxiliary information for the doctor's diagnosis, which is of great value for guiding clinical treatment. The purpose of this article is to explore the application value of combined detection of abnormal sugar-chain glycoprotein (TAP) and carcinoembryonic antigen (CEA) in the risk estimation of thyroid cancer in patients with thyroid nodules of type IV and above based on deep learning medical images. In this paper, ultrasound thyroid images are used as the research content, and the active contour level set method is used as the segmentation basis, and a segmentation algorithm for thyroid nodules is proposed. This paper takes ultrasound thyroid images as the research content, uses the active contour level set method as the basis of segmentation, and proposes an image segmentation algorithm Fast-SegNet based on deep learning, which extends the network model that was mainly used for thyroid medical image segmentation to more scenarios of the segmentation task. From January 2019 to October 2020, 400 patients with thyroid nodules of type IV and above were selected for physical examination and screening at the Health Management Center of our hospital, and they were diagnosed as thyroid cancer by pathological examination of thyroid nodules under B-ultrasound positioning. The detection rates of thyroid cancer in patients with thyroid nodules of type IV and above are compared; serum TAP and CEA levels are detected; PT-PCR is used to detect TTF-1, PTEN, and NIS expression; the detection, missed diagnosis, misdiagnosis rate, and diagnostic efficiency of the three detection methods are compared. This article uses the thyroid nodule region segmented based on deep learning medical images and compares experiments with CV model, LBF model, and DRLSE model. The experimental results show that the segmentation overlap rate of this method is as high as 98.4%, indicating that the algorithm proposed in this paper can more accurately extract the thyroid nodule area.

SMARCA4-mutated lung adenocarcinoma, a distinctive non-small cell lung cancer with worse prognosis.

e20548 Background: SMARCA4 gene is one of the catalytic subunits of the SWI/SNF chromosomal remodeling complex, which can regulate important cellular processes and functions and is closely associated to tumors. The clinical features, therapeutic efficacy, prognosis and pathological features of lung adenocarcinoma with this genetic variation are still unknown and controversial. Methods: The study recruited 274 patients (pts) with lung adenocarcinoma whose samples were sent to perform parallel hybridization-based next-generation sequencing. Two categories of SMARCA4 mutations were divided into Type1 mutations (frameshift mutations, nonsense mutations, splice-3 mutations, copy number amplification) and Type2 mutations (missense mutations and copy number loss) based on whether the mutation may result in defective protein. Furthermore, comparative analysis by using the clinical outcome data, the genomic and pathological characteristics were be performed in SMARCA4 Type 1 alterations corhort and Type 2 alterations corhort. Results: Among 274 pts were recruited, the mutation rate of SMARCA4 gene in lung adenocarcinoma was 9.1%. Furthermore, the presence of SMARCA4 alteration was associated with smoking (P＜0.05). Missense, nonsense, frameshift and splice were the most common types of mutations (92%). The pts with SMARCA4 Type1 alterations which probably lead to defective protein expression, had a worse prognosis compared with pts with SMARCA4 Type1 alterations (The role leading to defective protein expression is uncertain) and SMARCA4 Wild groups (P＜0.05). In addition, EGFR alterations were strongly associated with SMARCA4 Wild corhort compared to SMARCA4 Type1 alterations corhort (67% vs. 31% ), and SMARCA4 Type1 alterations was more associated with the absence of TP53, RB1, and Robo3 alterations. GO enrichment analysis suggested that the differentiated mutated genes between SMARCA4 Type1 alterations corhort and SMARCA4 Wild corhort were mainly enriched in cell cycle regulation. Pathologically, The SMARCA4 Type1 alterations was mostly poorly or moderately differentiated and strongly accompanied by the loss of expression of TTF-1(83.3%) and BRG1(80%) in immunohistochemistry. Conclusions: SMARCA4 Type1 alterations which probably lead to abnormality of protein was associated with poor prognosis and having different the genomic and pathological characteristics.