TTF-1 Positivity Research Articles

Clinicopathological correlation of three cases of metastatic carcinoma to uterine cervix: An institutional experience

Abstract Introduction/Objective Metastasis to the female genital tract presents a rare occurrence and poses significant diagnostic hurdles. The uterine cervix, although less frequently implicated, presents additional challenges for metastatic spread owing to its diminutive dimensions, limited vascular perfusion, and abundance of fibrous tissue. Clinical manifestations often include abnormal vaginal bleeding in 62–75% of cases, frequently accompanied by involvement in other anatomical sites. Accurate identification of cervical tumor activity and its primary origin holds paramount importance for precise diagnosis, therapeutic stratagem, and prognostic assessment. Methods/Case Report Here we are reporting three cases that were encountered in our institution over a 5-year period. The first patient, a 63-year-old female with a history of breast cancer, six years later exhibited metastatic breast cancer in a cervical polyp, confirmed by positivity for AE1/AE3, GATA3, ER, and negativity for TTF-1, chromogranin, synaptophysin, PAX8, inhibin, calretinin, CDX-2, CD10, desmin, smooth muscle actin, S100, and HMB-45. The second patient, diagnosed with pancreatic adenocarcinoma, two years later manifested cervical metastasis confirmed via positive staining for CK7, CDX2, and focal p63, and did not express PAX8, vimentin, ER, p16, synaptophysin, and chromogranin. The third patient, diagnosed with lung adenocarcinoma, one year later presented with a cervical mass, histologically confirmed as metastatic lung adenocarcinoma via positivity for CK7, Napsin A, and TTF1, and negativity for PAX8, p16, p40, p53, GATA3, and ER. Results (if a Case Study enter NA) N/A Conclusion Given the challenges of identifying metastasis to the cervix, thorough diagnostic evaluation should be undertaken to differentiate primary versus metastatic disease in women with a history of non-cervical malignancy.

Conclusive evidence for the origin of the carcinoid component in strumal carcinoids and a new morphological pattern

Abstract Introduction/Objective There has been debate whether strumal carcinoids are carcinoids with areas resembling thyroid or arise from bonafide thyroid tissue in struma. While the thyroid nature has been proven by demonstrating positive TTF-1 in the struma component, evidence for the origin of the carcinoid component is sparse. Herein, we describe a case of strumal carcinoid and use a panel of markers to show definitive morphological and immunohistochemical evidence of the evolution of the neoplasm from struma ovarii to struma carcinoid, within the same lesion. We also report a unique component of a more sinister single cell pattern of invasion apart from the usual insular, trabecular, and mucinous patterns. Methods/Case Report A 40-year-old woman with an adnexal mass underwent bilateral salpingo- oophorectomy/hysterectomy. Microscopic analysis identified thyroid tissue consistent with struma ovarii, juxtaposed with a neuroendocrine neoplasm. The interface between the two showed strong PAX-8 and uniform TTF-1 staining in the struma but gradual loss of TTF-1 with retained/weak PAX-8 staining, moving away from the struma component and into the carcinoid. Additionally, a pattern of single cell invasion was identified, away from the main tumor and at the ovarian surface. These cells closely resemble luteinized ovarian stromal cells but are stained like the carcinoid tumor. Two months postoperatively, the patient had no evidence of recurrence or metastasis. Results (if a Case Study enter NA) NA Conclusion We have provided conclusive morphological and immunohistochemical evidence that strumal carcinoid develops from native neuroendocrine cells of thyroid tissue in struma ovarii. Specifically, retained/weak PAX-8 with interspersed TTF-1 in an adnexal carcinoid provides valuable insight when dealing with tumors of unknown etiology, strongly favoring an ovarian primary (specifically, from struma ovarii) and not metastasis from the gastrointestinal tract or other Mullerian tissue. Lastly, the single cell pattern of invasion that we elucidate here is something to be aware of in the context of metastases or frozen sections.

7357 Microscopic Papillary Thyroid Cancer Presenting with Cranial Nerve Palsies due to Metastatic Cervical Lymphadenopathy: A Case Report

Abstract Disclosure: N.N. Mukhtar: None. C. Zuo: None. B.R. Haugen: None. Introduction: Tumors metastasizing to head and neck are considered a rare cause of cranial nerve palsy (CNP). In this report, we describe an unusual presentation of metastatic microscopic follicular variant papillary thyroid cancer (FVPTC) presenting with CNP. Case Summary: A 68-year-old previously healthy female presented to her primary care physician with a 6-week history of difficulty speaking and chewing food. She did not notice any dysphagia, change in voice or shortness of breath. Cranial nerve examination was evident for palatal asymmetry, left-sided uvular and right-sided tongue deviations suggesting right glossopharyngeal and hypoglossal nerve palsies. Neck examination revealed a normal thyroid gland without palpable nodules however, the patient had multiple enlarged painless right cervical lymph nodes (CLN). MRI of the brain was normal. CT of the neck and chest showed enlarged, calcified right level II and III CLN (largest 4x3.5 cm) compressing the right internal jugular vein. In addition, bilateral pulmonary nodules (largest 1.7x1.5 cm) suspicious for metastasis were seen. CT-guided biopsy of left upper lobe lung nodule was consistent with metastatic thyroid cancer (positive PAX-8 and TTF-1 immunostaining). Neck ultrasound did not show any thyroid nodules, but did confirm 4 enlarged right CLN (largest 2.9 cm). The patient was referred to our multidisciplinary clinic for further evaluation. Based on the duration of her symptoms (6 weeks), her CNP was most-likely irreversible and agreement to proceed with total thyroidectomy, central and right lateral neck dissection aiming for complete resection in preparation for future treatment with radioactive iodine. Preoperative thyroglobulin level was 30.7 ng/ml (1.6-50), thyroglobulin antibody 24 U/mL (<40) and TSH 0.6 mIU/L (0.4-4.6). Intra-operatively; the patient had extensive, bulky lymphadenopathy extending to surrounding neck muscles and completely encasing right jugular vein. Histopathological examination of the resected tissue showed a unifocal right thyroid lobe microscopic (6x4x3 mm) infiltrative follicular variant papillary thyroid cancer (FVPTC). No extrathyroidal extension, necrosis, angioinvasion or lymphatic invasion were identified. Mitotic index was 3/ 2mm2. 13 out of 36 lymph nodes were positive for metastatic thyroid cancer (3/3 level II, 2/17 level III, 8/16 level IV), largest was 4.6 cm with extra-nodal extension. The patient was discharged on suppressive dose levothyroxine. Molecular studies: Next generation sequencing of the lung biopsy was negative for BRAFV[6]00E mutation and further molecular analyses are ongoing. Conclusion: This case describes two unique presentations of thyroid cancer; a microscopic FVPTC associated with large lateral cervical lymph node metastasis and, CNP as the initial presentation of thyroid cancer which to our knowledge, has not been reported previously. Presentation: 6/2/2024

S2676 First Reported Case of Primary Small Cell Cancer of the Pancreas With Positive TTF-1 Tumor Marker

S2676 First Reported Case of Primary Small Cell Cancer of the Pancreas With Positive TTF-1 Tumor Marker

Clinicopathological and Immunohistochemical Analysis of Lung Cancer Biopsies at a Tertiary Care Centre in Central Gujarat, India

Introduction: Lung biopsy is a reliable and highly accurate tool for diagnosing and subtyping lung lesions. Two-thirds of lung cancer patients present with advanced disease, and small biopsies remain the main diagnostic tool. Histopathological and immunohistochemical examination of lung biopsies plays an important role in accurately diagnosing lung malignancies. Aim: The aim of present study was to analyse the clinicopathological and immunohistochemical features of lung cancer. Materials and Methods: This cross-sectional study was conducted in the Department of Pathology, Medical College, Baroda, over a period of two years and three months, from March 2019 to May 2021. A total of 53 cases of malignant lung cancer biopsies were included in this study. Clinical parameters, such as patient age, complaints, smoking history, clinical presentation, radiological findings, histopathology reports, and IHC findings, were retrieved. All cases underwent histopathological examination, and tumour typing was done according to the WHO classification 2021 of lung tumours. Immunohistochemistry (IHC) markers like CK5/6, CK7, TTF1, P63, synaptophysin, chromogranin, and pankeratin were used for further subtyping. Data analysis was done by Microsoft Excel 2019 spreadsheet. Results: A total of 53 cases of malignant lung cancer were included in this study. Of these, 38 (71.69%) cases were male, and 15 (28.30%) cases were female. 43 (81.13%) cases were over 50 years old, with a mean age of 61 years. After IHC, adenocarcinoma was seen in 27 cases (50.9%), followed by Squamous Cell Carcinoma (SCC) in 19 cases (35.8%), five cases of small cell carcinoma, one case of large cell neuroendocrine carcinoma, and one case of Non Small Cell Carcinoma-Not Otherwise Specified (NSCC-NOS). In adenocarcinoma, positivity for CK7, TTF1, and p63 was 100%, 74.07%, and 16.6%, respectively. In squamous cell carcinoma, positivity for CK5/6 and p63 was 100% and 78.94%, respectively. Conclusion: In the present study, the majority of cases were males. Adenocarcinoma was the most common subtype of Non Small Cell Lung Cancer (NSCLC). A panel of IHC markers is helpful in differentiating NSCLC into adenocarcinoma and squamous cell carcinoma on small true-cut lung biopsies. CK5/6 and p63 aid in detecting squamous cell carcinoma, while CK7 and TTF-1 help in detecting adenocarcinoma. The recommended immunohistochemical profile for NSCLC includes TTF1, CK5/6, CK7, and p63.

Neoplasms in Struma Ovarii: A Review.

Struma ovarii is a well-known ovarian teratoma made up of benign thyroid tissue. These lesions demonstrate variable, normal architecture and normal thyroid immunohistochemical staining with positivity for TTF1, PAX8, and thyroglobulin. Though most are benign, some of these lesions can also present with a malignant component. Within this article, we review the most common diagnostic malignancies including papillary thyroid carcinoma, strumal carcinoid, highly differentiated follicular thyroid carcinoma, and other thyroid carcinomas. We additionally review the use of TTF1 staining to assist in differentiating these lesions from surrounding gynecologic epithelium, which is imperative in making such diagnoses. In highlighting these entities, we hope to provide practicing pathologists with an effective and concise review of these lesions to assist in more challenging cases of struma ovarii.

Predictive Impact of Diffuse Positivity for TTF-1 Expression in Patients Treated With Platinum-Doublet Chemotherapy Plus Immune Checkpoint Inhibitors for Advanced Nonsquamous NSCLC

IntroductionPervious studies reported the association of TTF-1 expression with the efficacy of platinum-doublet chemotherapy in combination with immune checkpoint inhibitors in advanced nonsquamous NSCLC. Nevertheless, the predictive value of extent of TTF-1 expression (diffuse or focal TTF-1 positivity) remains unclear. MethodsThe present study retrospectively reviewed 74 patients with TTF-1–positive recurrent or advanced nonsquamous NSCLC receiving first-line chemoimmunotherapy in a single institution in Japan. TTF-1 expression score in pretreatment tumor specimens was evaluated using immunohistochemistry, and the impact of chemoimmunotherapy response was analyzed. ResultsIn the total cohort, ≥50% of the tumor cells were TTF-1 positive (i.e., diffusely TTF-1 positive) in specimens of 61 patients (82.4%), whereas 10% to 49% of the tumor cells were TTF-1 positive (i.e., focally TTF-1 positive) in specimens of the remaining 13 patients (17.6%). In multivariate analysis, the median progression-free survival and overall survival (OS) were significantly longer in patients with diffusely TTF-1–positive tumors than in those with focally TTF-1–positive tumors (14.2 versus 9.2 mo, p = 0.01 and 30.2 versus 17.3 mo, p = 0.01, respectively). Moreover, the median OS was significantly longer in patients receiving chemoimmunotherapy including pemetrexed than in those receiving chemoimmunotherapy not including pemetrexed among the patients with diffusely TTF-1–positive tumors (not attained versus 23.2 mo, p < 0.01). ConclusionsThe positive extent of diffuse TTF-1 expression associated with patient outcome was an independent predictive factor for better progression-free survival and OS in patients with advanced nonsquamous NSCLC receiving chemoimmunotherapy.

Real-World Evidence of EGFR Targeted Therapy in NSCLC– A Brief Report of Decade Long Single Center Experience

The significance of EGFR targeted therapy in the lung adenocarcinoma is paramount. Several controlled clinical trials have reported considerable survival of EGFR mutation positive patients on receiving the EGFR tyrosine kinase inhibitor (TKI). However, the real-world evidence of benefits of EGFR TKI would be further useful to understand how the designated therapeutic regimen benefits the patients. In this study, we report a decade long real-world evidence of EGFR molecular testing in lung cancer at Tata Memorial Hospital (Mumbai, India). Laboratory and hospital records containing basic demographic details, clinical characteristics, treatment regimen, survival outcome were collected retrospectively. Statistical association and survival analysis were performed using the R programming. The cohort includes 9,053 lung cancer patients tested for EGFR mutations during 2011 to 2019. Baseline T790M and compound mutations were the only mutations observed co-occurring while all other EGFR mutations were mutually exclusive. Furthermore, the baseline T790M were also observed to be associated with TTF1 positivity, smoking and local metastasis. Overall survival of the patients harboring co-occurring compound mutations was significantly lesser than the other EGFR positive patients. Overall, our study suggests that EGFR TKI may provide real-world benefit to the lung cancer patients harboring mutually exclusive EGFR mutations. On the other hand, further systematic study is essential to develop better therapeutic regimen for co-occurring baseline EGFR T790M and other compound mutations.

Incidental Thyroid Tissue in Sentinel Nodes From Oral Squamous Cell Carcinoma.

Sentinel node biopsy (SNB) is a surgical staging test in which sentinel nodes (SNs) undergo intensive histological analysis. SNB diagnoses early cancer spread, but can also reveal unexpected findings within the SNs. We review cases of incidental thyroid cells (TC) found in SNs from patients with oral squamous cell carcinoma (OSCC) to assess the prevalence of TC, and the clinical significance of these. Multicenter retrospective review of SNB performed for cT1-T2N0 OSCC. Incidental TC were identified by TTF-1 or thyroglobulin positivity. Anatomical location of nodes containing TC, TC morphology, and ongoing management/follow up of this incidental finding was recorded. Neck dissections performed during the same period were reviewed to establish the expected incidence of TC in neck nodes without serial sectioning analysis. 278 SNB cases were reviewed. Ten procedures detected TC in nine patients (10/278, 3.6%). During the same time period 725 neck dissections were performed, six containing TCs (6/725, 0.8%). One patient underwent SNB twice with TC identified on both occasions. Three patients had both OSCC metastasis and thyroid cells. All SNB patients with TC identified underwent thyroid USS with no primary tumours identified. Three patients underwent thyroidectomy, in all cases no primary thyroid tumour was found. Prevalence of incidental TC in SNs appears to be higher than that reported in neck dissections, these are not likely to be clinically relevant and can be managed on a conservative basis in the absence of clear metastatic features. Multicentre retrospective cohort study, 3 Laryngoscope, 134:1278-1281, 2024.

Metastasis of Pulmonary Carcinoma to the Breast: Case Report

Introduction: Pulmonary carcinoma is the most prevalent cancer in the world, followed by breast cancer. It has high mortality rates in men and women mainly due to its ability to metastasize. Metastases from lung carcinoma to the breast are extremely rare. The first case described occurred in 1965 and since then there are few cases of this condition reported in the world medical literature. Case report: A 59-year-old woman who complained of low back pain in May 2017. The investigation revealed a metastatic site in the fifth vertebra of the lumbar spine with unknown origin. Six months later, a new lesion was found in the ninth vertebra of the thoracic spine. Immunohistochemistry showed positivity for cytokeratin 7 and TTF1 markers, confirming the hypothesis of lung carcinoma as the primary site. In March 2018, the patient evolved with a symptomatic nodule in the right breast on ultrasound and with positivity for TTF1 on immunohistochemical study, confirming the metastasis of lung carcinoma to the breast. Treated for two years until March 2020, when she presented multiple brain metastases. Patient had no therapeutic success and died. Conclusion: The difficulty in diagnosing lung carcinoma metastasis to the breast stands out, surgeons, clinicians and pathologists should consider this diagnosis, although rare.

The Prognostic Value of TTF-1/NKX2-1 in Lung Squamous Cell Carcinoma.

TTF-1/NKX2-1 is a lineage-specific transcription factor that is expressed in the thyroid gland, lung, and forehead. It functions as a key component in regulating lung morphogenesis and differentiation. It is mainly expressed in lung adenocarcinoma, while its prognostic value in non-small-cell lung cancer remains controversial. This study evaluates the prognostic value of TTF-1 in different cellular locations in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC). The expression of TTF-1 was analyzed by immunohistochemistry in 492 patients (ADC 340 and SCC 152) who had undergone surgery between June 2004 and June 2012. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Positive TTF-1 expression was 68.2% in ADC (located in the nucleus) and 29.6% in SCC (cytoplasm staining). The presence of TTF-1 was associated with better OS in SCC and ADC (P=0.000 and P=0.003, respectively). In SCC, an increased level of TTF-1 was associated with a longer disease-free survival (DFS). Positive TTF-1 expression was an independent favorable prognostic factor in SCC (P=0.020, HR: 2.789, 95%CI: 1.172-6.637) and ADC (P=0.025, HR: 1.680, 95%CI: 1.069-2.641). TTF-1 was largely located in the nucleus of ADC, while it always accumulated in the cytoplasm of SCC. The higher level of TTF-1 in the different subcellular locations of ADC and SCC was an independent, favorable prognostic factor, respectively. Increased TTF-1 in the cytoplasm of SCC was associated with a longer OS and DFS.

Thoracic SMARCA4-deficient undifferentiated tumor: A clinicopathologic study.

e14642 Background: Thoracic SMARCA4-deficient undifferentiated tumor is a high-grade malignant neoplasm that frequently shows undifferentiated morphology and deficiency of SMARCA4. There is limited data in literature for this entity. The purpose of this report is to describe clinicopathologic features of this rare tumor in a series of 5 patients, diagnosed and treated at our institution. Methods: After approval from institutional review board, pathology department archive was searched for the patients with diagnosis of Thoracic SMARCA4-deficient undifferentiated tumor from January 2020 to December 2022. Data such as patient demographics, pathologic features including immunohistochemical stains, treatment and clinical outcome were collected. Results: Among 5 patients, 3 were male and 2 were female. Median age was 62 years (range 49 to 77 years). In three patients the primary site of the tumor was lung. One patient had tumor of the gastroesophageal junction while one patient had epicenter of the tumor in the paraspinous muscle. Diagnosis was made on biopsy specimen in all cases. All tumor showed undifferentiated histologic appearance. Rare cells with keratin positivity were observed in 2 specimens while 3 were completely negative for keratin stains. Focal TTF1 positivity was observed in one specimen while 4 were negative. Among neuroendocrine markers performed on variable number of cases, synaptophysin was positive in 4/4 cases while chromogranin was negative in 2/2 cases and INSM1 was negative in 1/1 case. PD-L1 (Dako 22C3) was performed on two specimens and showed less than 1% tumor cells to be positive. Next generation sequencing was performed on one specimen and showed pathogenic variants in TP53, CDKN2A, and APC genes and likely pathogenic variants in ATR, SMARCA4, and BCOR genes. Two patients received carbotaxol and radiation, one patient received FOLFOX, nivolumab and radiation, 1 patient pursued hospice care and 1 patient lost follow up. Two patients died 2 and 7 months after diagnosis. One patient is alive with metastatic disease 4 months after initial diagnosis. Conclusions: SMARCA4-deficient undifferentiated tumor is an aggressive malignancy that shows undifferentiated histology with synaptophysin positivity. From a diagnosis standpoint, Pathologists need to keep this entity in mind while working up tumors showing poorly differentiated to undifferentiated histology that are negative for most immunohistochemical markers. From clinical standpoint there is need to develop targeted therapy for this aggressive tumor.

Expression landscapes in non-small cell lung cancer shaped by the thyroid transcription factor 1

TTF-1-expressing non-small cell lung cancer (NSCLC) is one of the most prevalent lung cancer types worldwide. However, theparadoxical activity of TTF-1 in both lung carcinogenesis and tumor suppression is believed to be context-dependentwhich calls for a deeper understanding about the pathological expression of TTF-1. In addition, the expression circuitry of TTF-1-target genes in NSCLC has not been well examined which necessitates to revisit the involvement of TTF-1- in a multitude of oncologic pathways. We used RNA-seq and clinical data of patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), including ChIP-seq data from different NSCLC cell lines, and mapped the proteome of NSCLC tumor. Our analysis showed significant variability in TTF-1 expression among NSCLC,and further clarified that this variability is orchestrated at the transcriptional level. We also found that high TTF-1 expression could negatively influence the survival outcomes of stage 1 LUAD which may be attributed to growth factor receptor-driven activation of mitogenic and angiogenic pathways. Mechanistically, TTF-1 may also control the genes associated with pathways involved in acquired TKI drug resistance or response to immune checkpoint inhibitors. Lastly, proteome-based biomarker discovery in stage 1 LUAD showed that TTF-1 positivity is potentially associated with the upregulation of several oncogenes which includes interferon proteins, MUC1, STAT3, and EIF2AK2. Collectively, this study highlights the potential involvement of TTF-1 in cell proliferation, immune evasion, and angiogenesis in early-stage NSCLC.

ODP303 Cushing's Syndrome Due to Ectopic Adrenocorticotropic Hormone-Secreting Metastatic Neuroendocrine Tumor

Abstract Introduction Cushing's syndrome (CS) due to ectopic ACTH secretion (EAS), is an infrequent form of ACTH-dependent CS. EAS results from unregulated ACTH secretion by neuroendocrine tumors (NETs) of various locations resulting in severe hypercortisolism. The progression of CS is usually precipitous. To improve outcomes, it is imperative to recognize early so that treatments of cortisol-induced comorbidities and targeted treatments can be initiated. Case Presentation A 74-year-old female presented to an outside hospital with fatigue, bilateral lower extremity edema and intractable hypokalemia. She was later transferred to our facility, where workup of CS was initiated. She underwent a 1mgdexamethasone suppression test (DST)which resulted in an unsuppressed 8amcortisol of 34.7 ug/dL (&amp;lt;2 ug/dL). This was followed by a 4mgDST, again resulting in an unsuppressed 8amcortisol of25.4 ug/dL. A 24-hour urine cortisol level was collected and resulted at 2,108.9 ug/d (&amp;lt;45 ug/d). ACTH level was elevated at 136 pg/ml (7.2-63.3 pg/ml). CT abdomen/pelvis identified liver lesions concerning for metastatic disease. PET DOTATATE revealed multiple liver lesions and a few pulmonary nodules. Biopsy of liver lesions demonstrated strongly positive staining of synaptophysin and chromogranin confirming NET, with a weak TTF-1 positivity suggestive of pulmonary origin. Lanreotide injections were initiated for tumor control and ketoconazole for treatment of persistent hypercortisolism. Despite titration of ketoconazole, symptoms and labs showed minimal improvement. Osilodrostat was then added as a third line and examethasone was initiated in a block and replace approach. The regimen of lanreotide, osilodrostat and ketoconazole improved her24-hoururine cortisol to 15 from 2,109 ug/24hr. Subsequently patient underwent trans-arterial chemoembolization (TACE) of the liver lesions with resolution of hypercortisolism. She is currently only on Lanreotide for tumor control. Discussion NET with ectopic ACTH production is rare. While primary tumor location was not definitively identified, multiple lung lesions and histopathology suggested primary lung tumor with hepatic metastases. 20-40% of all NETS originate in the chest. Patient management necessitates a multidisciplinary approach not only for the diagnosis and treatment of CS but also for the specific management of neuroendocrine tumors (NET). This case highlights a rare presentation of EAS, and aggressive treatment modalities needed to treat symptoms of excess cortisol production and tumor progression. Presentation: No date and time listed

Lung carcinoid tumours: histology and Ki-67, the eternal rivalry.

WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated. A retrospective series of 370 LCT from two oncology centers was centrally reviewed. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR-2A, Ascl1, and p53) were studied and correlated with Overall Survival (OS), Cancer-specific survival (CSS) and Disease-free survival (DFS). Carcinoid histology was confirmed in 355 patients: 297 (83.7%) TC and 58 (16.3%) AC. Ki-67 at 3% was the best value in predicting DFS. Ki-67 ≥ 3% tumours were significantly associated with AC histology, stage III-IV, smoking, vascular invasion, tumour spread through air spaces OTP negativity, and TTF-1, Ascl1 and p53 positivity. After adjustment for center and period of diagnosis, both Ki-67 (≥3 versus <3) and histology (AC versus TC) alone significantly added prognostic information to OS and CSS multivariable model with age, stage and OTP; addition of both variables did not provide further prognostic information. Conversely, an improved significance of the DFS prediction model at multivariate analysis was seen by adding Ki-67 (≥3 versus <3, P adj=0.01) to TC and AC histological distinction, age, lymph node involvement, residual tumour and OTP. Ki-67 ≥ 3% plays a potentially pivotal role in LCT prognosis, irrespective of histological grade.

ADENOCARCINOMA OF THE LUNG MIMICKING MILIARY TB AND POTT DISEASE

ADENOCARCINOMA OF THE LUNG MIMICKING MILIARY TB AND POTT DISEASE

METASTATIC CARCINOMA WITH HEPATIC DIFFERENTIATION: A RARE CASE IN THE ORAL CAVITY

This study reports a case of an 81-year-old male patient with an ulcerative lesion in his mouth. The clinical hypothesis was squamous cell carcinoma. After an incisional biopsy was performed, the anatomopathologic diagnosis was of a malignant neoplasm with ulceration. An immunohistochemical study revealed positivity for hepatocyte (strong and diffuse) and cytoplasmic positivity for TTF1 and cytokeratin (AE/AE3). Differential diagnoses such as melanoma, primary pulmonary site, primary site of the gastrointestinal tract, malignant vascular neoplasms, and primary adrenal site were discarded. These aspects were based on the negative expression of markers (CK7, CK20, CD31, ERG, CD45, Melan-A, CD34, S-100, p63, and CDX2). These findings are consistent with the diagnosis of a moderately differentiated metastatic carcinoma favoring an ulcerated hepatocellular carcinoma. The patient was referred for treatment at a referral service.

Anti-CK7/CK20 Immunohistochemistry Did Not Associate with the Metastatic Site in TTF-1-Negative Lung Cancer.

Anti-CK7 and anti-CK20 immunohistochemistry is sometimes used to establish a diagnosis of primary lung cancer. We performed a retrospective study on the value of anti-CK7 and anti-CK20 immunohistochemistry in 359 biopsies of patients with suspected lung carcinoma in order to assess the usefulness of these antibodies in the evaluation of lung tumors in biopsies. Our results showed TTF-1 positivity in 73.3% of patients. EGFR mutations and ALK rearrangements were significantly different between TTF-1 positive and TTF-1 negative tumors (p < 0.001 and p = 0.023, respectively). Our results show a significant difference (p < 0.001) between TTF-1 positive and TTF-1 negative carcinomas with a median survival of 21.97 months (CI95% = 17.48–30.9 months) and 6.52 months (CI95% = 3.34–10.3 months), respectively. In the group of TTF-1 negative patients, anti-CK7 and CK20 immunohistochemistry was performed in 70 patients and showed CK7+/CK20- staining in 61 patients (87.1%), CK7-/CK20- in 4 patients (5.7%), CK7+/CK20+ in 3 patients (4.3%), and CK7-/CK20- in 2 patients (2.8%). No specific or molecular pattern was found in these groups of CK7/CK20 combinations. In total, this work brings arguments concerning the uselessness of anti-CK7/CK20 immunohistochemistry in the case of suspicion of primary lung cancer in biopsies.

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 &amp;gt;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(&amp;lt;70, ≥70), sex, smoking history, number of metastatic lesions (&amp;lt;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.

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 &lt; 0.01]. The progression-free survival(PFS) also showed a statistically significant difference in patients (non-HPD vs HPD) [OR = 3.4, P &lt; 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 &gt; 450k) [OR = 5.31, P &lt; 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(&lt; 70, ≥70), sex, smoking history, number of metastatic lesions (&lt; 3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, TNM staging, tumor mutational burden (TMB) (&lt; 10, ≥10), microsatellite stability index (MSI), human leukocyte antigen-1 (HLA-1) heterozygosity, hemoglobin(≤12, &gt; 12), albumin(≤3.5, &gt; 3.5), and LDH(≤240, &gt; 240). Conclusions: The incidence of HPD, 16%, was consistent with current literature. NLR ≥5, platelet count &gt; 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.