GATA3 is a useful immunohistochemical marker for distinguishing sarcomatoid malignant mesothelioma from lung sarcomatoid carcinoma and organizing pleuritis.

Sarcomatoid malignant mesothelioma (SMM) tends to occur in the pleura and is morphologically similar to lung sarcomatoid carcinoma (LSC) and organizing pleuritis (OP). Because SMM often does not express mesothelial markers, it is very difficult to distinguish from LSC and OP. GATA-binding protein 3 (GATA3) is a specific immunohistochemical (IHC) marker of breast and urothelial carcinoma. We routinely find that GATA is expressed in MM; however, GATA3 expression in SMM and its reference value for distinguishing SMM from LSC and OP remain unclear. Here, we used IHC methods to detect the expression of GATA3 and classic mesothelial markers in 17 SMM, 12 LSC, and 7 OP cases. We detected the following expression rates in SMM versus LSC cases: GATA3 (70.6% vs. 16.7%, p = 0.008), calretinin (52.9% vs. 8.3%, p = 0.019), Wilms tumor (WT)-1 (64.7% vs. 0%, p = 0.000), D2-40 (47.1% vs. 16.7%, p = 0.126), CK5/6 (35.3% vs. 25.0%, p = 0.694), and pan-cytokeratin (CKpan) (88.2% vs. 100.0%, p = 0.498). The specificities of calretinin, WT-1, and GATA3 in distinguishing SMM from LSC were 91.7%, 100%, and 83.3%, respectively, and combinations of any two of these three markers exhibited 100% specificity for SMM. Notably, the sensitivity of calretinin+/WT1+ staining for SMM was only 23.5%, which increased to 64.7% after including GATA3. Furthermore, all OP cases showed partial or diffuse expression of CKpan, WT-1, and D2-40 but no GATA3 and calretinin expression. In conclusion, GATA3 is an IHC marker with excellent sensitivity and specificity for SMM, and the combined consideration of GATA3, calretinin, and WT-1 was best for distinguishing SMM from LSC. Moreover, CKpan, WT-1, and D2-40 had no value for distinguishing SMM from OP, and GATA3 and calretinin were the most specific markers for distinguishing these two lesions.

Synchronous primary lung sarcomatous carcinoma and lung squamous cell carcinoma: a case report.

Sarcomatoid carcinoma (SC) is a rare primary malignant tumor, which seldom occurs in the lung, let alone as synchronous primary lung sarcomatous carcinoma and lung squamous cell carcinoma. We present a case of a 65-year-old Chinese man with a three-month history of cough and expectoration. The diagnosis was a combination of poorly differentiated synchronous central type primary lung sarcomatous carcinoma and lung squamous cell carcinoma with approximately 50% proportion of each, and the TNM classification was pT2aN1M0, at least AJCC Stage IIA. The purpose of the case report is to present the imaging, pathologic features, and treatment.

CD8+ tumor-infiltrating lymphocytes as a novel prognostic biomarker in lung sarcomatoid carcinoma, a rare subtype of lung cancer.

PURPOSE: The aim of this study was to investigate the degree of infiltration of CD8+ tumor-infiltrating lymphocytes (TILs) including high and low density in lung sarcomatoid carcinoma (LSC) and their clinicopathological significance. PATIENTS AND METHODS: The density of CD8+ TILs in paraffin-embedded tissue sections from 100 LSC patients was detected by immunohistochemical staining, and the relationship of CD8+ TILs with clinicopathological features and prognosis was analyzed. RESULTS: The chi-squared test showed that the degree of infiltration of CD8+ TILs was significantly correlated with the clinicopathological stage and T stage of LSC (P<0.05). The univariate analysis demonstrated that tumor size, clinicopathological stage, T stage, N stage, M stage, and CD8+ TILs are risk factors that affect prognosis of the patients (P<0.05). The mean overall survival (OS) of LSC patients with a high density of CD8+ TILs was 92.3 months, which was significantly higher than 31.2 months in patients with a low density of CD8+ TILs (P<0.05). Cox regression multivariate analysis confirmed that the density of CD8+ TILs was an independent prognostic factor for OS time of LSC patients (hazard ratio=0.455, P<0.05). CONCLUSION: CD8+ TILs could be used as an effective prognostic index for LSC patients, and a high density of CD8+ TILs in tumor tissue may predict a better outcome.

c-MET Overexpression as a Poor Predictor of MET Amplifications or Exon 14 Mutations in Lung Sarcomatoid Carcinomas.

INTRODUCTION: MNNG HOS transforming gene (MET) abnormalities such as amplification and exon 14 mutations may be responsive to targeted therapies. They are prevalent in lung sarcomatoid carcinomas (LSCs) and must be diagnosed as efficiently as possible. Hypothetically, c-MET overexpression by immunohistochemistry (IHC) may prove effective as a screening test for MET abnormalities. METHODS: Tissue samples were obtained from consecutive patients with a resected LSC in four oncologic centers. IHC was performed using the SP44 antibody (Ventana, Tucson, Arizona) and evaluated using the MetMab score and H-score. Fluorescence in situ hybridization was applied with the dual color probe set from Zytovision (Clinisciences, Nanterre, France). True MET amplification was diagnosed when MET gene copy number was 5 or greater and the ratio between MET gene copy number and chromosome 7 number was greater than 2. All MET exon 14 alterations including those affecting splice sites occurring within splice donor and acceptor sites were detected in the routine molecular testing on genetic platforms. RESULTS: A total of 81 LSCs were included. Fourteen (17%) exhibited positive IHC using the MetMab score and 15 (18.5%) using the H-score. MET amplification was detected in six tumors (8.5%) and MET exon 14 mutation in five (6%). A weak positive correlation between IHC and fluorescence in situ hybridization was found (r = 0.27, p = 0.0001). IHC sensitivity for MET amplification was 50%, with a specificity of 83%, positive predictive value of 21.4%, and negative predictive value of 94.7%. IHC sensitivity for MET exon 14 mutations was 20%, with a specificity of 83%, positive predictive value of 7%, and negative predictive value of 94%. CONCLUSION: IHC is not a relevant screening tool for MET abnormalities in LSC.

[Expression of anaplastic lymphoma kinase fusion gene in patients with lung sarcomatoid carcinoma and treatment analysis].

Objective: To investigate the expression status of anaplastic lymphoma kinase (ALK) fusion gene in lung sarcomatoid carcinoma (LSC) and the role of ALK inhibitors for treatment. Methods: Total of 84 cases of LSC confirmed by histopathology were detected for ALK fusion gene from January 2011 to December 2014 in the Cancer Hospital of Chinese Academy of Medical Science&Peking Union Medical College and Shandong Zibo Wanjie Cancer Hospital. All patients were primarily treated by the multi-disciplinary mode in combination with chemotherapy or targeted therapy based on surgery. Postoperative adjuvant chemotherapy was given on platinum based two-drug combination regimen. In ALK fusion gene (+ ) patients with recurrence or metastasis, crizotinib target therapy was prefered. Chi-square test was applied for the comparison of 1, 3, 5-year survival rates between the two groups. Results: Eighty-two cases completed the follow-up. ALK fusion gene was found in 9(10.7%) patients. After application of crizotinib, 1 case was evaluated as complete remission, 6 cases as partial response, 2 cases as stable disease; the 1, 3, 5-year survival rate was 100% (9/9), 100% (9/9) and 88.9% (8/9) for the patients with ALK fusion gene, and it was 65.8% (48/73), 15.1% (11/73) and 6.8% (5/73) respectively for patients without ALK fusion gene. There was significant difference in the survival rate between the two groups (χ(2)=1.56, 1.56, 0.83, all P<0.05). Conclusion: ALK fusion gene maybe expressed in LSC patients. Compared with conventional chemotherapy, crizotinib can significantly prolong the survival time of patients with ALK fusion gene.

Overexpression of p53R2 is associated with poor prognosis in lung sarcomatoid carcinoma.

BACKGROUND: This study aimmed to evaluate the expression of p53-inducible RR small subunit 2 homologue (p53R2) in Lung sarcomatoid carcinoma (LSC) and its association with clinicopathological parameters and prognosis. METHODS: In this study, clinicopathological factors and prognostic significance of the expression of p53R2 was investigated by immunohistochemistry (IHC) in 100 cases of LSC. RESULTS: The results showed that the expression of p53R2 was significantly correlated with clinical stage (P<0.05). But there was no statistically correlation with gender, age, smoking, tumor size, pT stage, pN stage, pM stage, therapy and relapse. Kaplan-Meier analysis revealed that the expression of p53R2, clinical stage, pT stage, pN stage, pM stage and tumor size were closely related to patients' survival, and the analysis also revealed that patients with low expression of p53R2 had a longer overall survival than that with high expression (Mean overall survival: 84.8 months vs. 34.7 months, P<0.05). Further multivariate analysis indicated that the expression of p53R2 was identified as an independent prognostic factor in the prediction of the overall survival for patients with LSC (HR = 3.217, P<0.05). CONCLUSIONS: The expression of p53R2 was inversely associated with the proliferation and progression of LSC, and the results indicated that the high expression of p53R2 was an independent factor for unfavorable prognosis of patients with LSC.

Extreme leukocytosis and leukemoid reaction associated with the lung sarcomatoid carcinoma: an unusual case report.

PURPOSE: To report a rare case of extreme leukocytosis and leukemoid reaction associated with lung sarcomatoid carcinoma (LSC) and increase people's awareness of the disease. PATIENTS AND METHODS: A 58-year-old male patient was diagnosed with LSC; however, after the end of the second course of chemotherapy, his white blood cells increased gradually without fever or use of medications such as granulocyte colony-stimulating factor and steroids. A bone marrow biopsy then confirmed it to be a leukemoid reaction. RESULTS: The patient died of multiple organ failure 2 months after being diagnosed with leukocytosis. CONCLUSION: LSC associated with leukemoid reaction is very rare and the prognosis is poor. When a patient's white blood cells are extremely elevated, we should think of the possible causes of the tumor itself and identify it with other diseases. However, more data and evidence are still needed to find an effective adjuvant therapy for these patients.

Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages.

OBJECTIVES: Pulmonary sarcomatoid carcinomas (SC) are rare tumors, associated with worse prognosis and resistant to platinum-based regimens. Therapies targeting the PD-1/PD-L1 pathway are an emerging treatment for lung cancer. By characterizing intra-tumoral immune infiltration and evaluating PD-L1 expression, it could be possible to predict the efficacy of these new treatments. MATERIALS AND METHODS: From 1997 to 2013, data from all patients with SC who underwent lung resection was collected. Tumor-immune infiltration and PD-L1 expression were studied by immunochemistry tests, analyzing CD3 (clone SP7), CD4 (clone 1F6), CD8 (clone C8/144b), CD20 (clone L26), CD163 (clone 10D6), MPO (clone 59A5), and PD-L1 (clone 5H1). Results were compared to those of 54 NSCLC. RESULTS: In total, 75 SC were included. Forty (53%) SC expressed PD-L1 vs 11 NSCLC (20%) (p<0.0001). CD3+ tumor-infiltrating lymphocytes and CD163+ tumor-associated macrophages were more important in SC than in NSCLC (median 23% [17-30] of tumoral surface vs 17% [7-27], p=0.011 and 23% [17-30] vs 20% [13-23], p=0.002, respectively). In SC, the presence of Kirsten Ras (KRAS) mutations, blood vessel invasion, and TTF1+ positivity were associated with PDL1 expression. On multivariate analysis, only CD163+ macrophages and blood-vessel invasion were associated with tumoral PD-L1 expression. High levels of tumor-infiltrating lymphocytes (CD3+ or CD4+ and not CD8+) constituted a factor of good prognosis on survival. Interestingly, PD-L1 expression distinguishes subpopulations within tumor-infiltrating lymphocytes (CD3+ or CD4+) with different prognosis CONCLUSIONS: PD-L1 expression was higher in SC than in NSCLC as well as immune-cell infiltration by TCD3 cells and macrophages. This suggests that targeting the PD-1/PD-L1 pathway could represent a new potential therapy.

High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta™ Panel: exploring therapeutic targets.

BACKGROUND: Pulmonary sarcomatoid carcinomas (SC) are tumors characterized by poor prognosis and resistance to conventional platinum-based chemotherapy. This study sought to describe the mutational profile of SC using high-throughput genotyping technology. PATIENTS AND METHODS: We used mass spectrometry to test 114 surgical biopsies from 81 patients with SC for 214 mutations affecting 26 oncogenes and tumor suppressor genes. RESULTS: In total, 75 (92.6%) patients were smokers. Within the total 81 tumors, 67 distinct somatic alterations were identified, with 56 tumors (69.1%) harboring at least one mutation. The most frequent mutations were KRAS (27.2%), EGFR (22.2%), TP53 (22.2%), STK11 (7.4%), NOTCH1 (4.9%), NRAS (4.9%), and PI3KCA (4.9%). The EGFR mutations were almost always rare mutations (89%). In 32 tumors (39.5%), two or more mutations co-existed, with up to four mutations in a single case. In six different cases, comparative genetic analysis of different histological areas from the same tumor (giant, spindle, or epithelial component) revealed a 61% concordance rate for all the mutations with a 10% detection threshold, compared with 91.7% with a 20% detection threshold. CONCLUSION: Our results demonstrated a high mutation rate and frequent co-mutations. Despite SC tumors exhibiting a high histological heterogeneity, some intratumoral molecular homogeneity was found. Now with newly developed targeted therapies, SC patients may be eligible for new target mutations, and can now therefore be screened for clinical trials.

Immunohistochemical study of 36 cases of pulmonary sarcomatoid carcinoma--sensitivity of TTF-1 is superior to napsin.

Immunohistochemistry is often used to distinguish pulmonary sarcomatoid carcinoma from morphologic mimics. Napsin-A is a pulmonary adenocarcinoma marker, but literature on expression in sarcomatoid carcinoma is limited. Thirty-six cases of sarcomatoid carcinoma were stained for napsin, TTF-1, Oscar, CAM5.2, AE1/AE3, desmin, SMA, S-100, CK5/6, calretinin, D2-40, and WT1. Patients were 24 men and 12 women (mean, 70 years; range, 46-93). There were 27 pleomorphic carcinomas, 5 spindle cell carcinomas, 3 carcinosarcomas, and 1 giant cell carcinoma. Cases were positive for at least 1 keratin: AE1/3 was positive in all 36 cases; Oscar, in 34 cases (94%); and CAM5.2, in 32 cases (89%, weaker/more focal). Napsin was positive in 14 cases (39%): 8 diffuse, 3 focal, and 3 rare cells. TTF-1 was positive in 22 cases (61%): 15 diffuse, 3 focal, and 4 rare cells. No cases were napsin positive and negative for TTF-1. Variable staining for mesothelial markers was observed, including positivity for calretinin (12 cases, 33%), WT1 (6 cases, 17%), D2-40 (5 cases, 14%), and CK5/6 (9 cases, 25%). Mesenchymal markers were also sometimes positive (usually focal), including S-100 (4 cases, 11%), desmin (4 cases, 11%), and SMA (7 cases, 19%, 1 diffuse). In conclusion, TTF-1 is more sensitive than napsin for detection of sarcomatoid carcinoma, and no cases were positive for napsin but negative for TTF-1. CAM5.2 is less sensitive than AE1/AE3 and Oscar. Use of a thoughtful immunohistochemical panel is important in the evaluation of sarcomatoid carcinoma because mesothelial and mesenchymal markers can be expressed.

The first case of lung carcinosarcoma harboring in-frame deletions at exon19 in the EGFR gene.

Mutations of the epidermal growth factor receptor (EGFR) gene play a critical role in carcinogenesis of lung cancer, particularly adenocarcinoma. However, to the best of our knowledge, no mutations of the EGFR in patients with lung carcinosarcoma have been identified. We herein report the case of a 61-year-old female referred for a detailed examination of a left pulmonary mass shadow. Although bronchoscopy was performed, it failed to lead to a diagnosis, and video-assisted thoracoscopic surgery was therefore carried out to diagnose the tumor. The pathology revealed biphasic features consisting of both adenocarcinoma and chondrosarcoma. Intriguingly, both the adenocarcinoma and chondrosarcoma components were proven to harbor an exon19 deletion in the EGFR gene. Although carcinosarcoma is a rare malignancy of the lungs, genetic analyses of oncogenic drivers, such as the EGFR gene, should be conducted.