Extracapsular extension of pN2 lymph node metastases is not prognostically significant in surgically resected patients with non-small cell lung cancer.

Objectives: In patients with non-small cell lung cancer (NSCLC) the pathologic lymph node status N2 is a heterogeneous entity, with different degrees of lymph node involvement representing different prognoses. It is speculated whether extra capsular nodal extension may help to define a subgroup with implications on long-term survival. Methods: We retrospectively identified 118 patients with non-small cell lung cancer (65 men, 53 women), who were treated between 2013 and 2018 and found to have pathologic N2 lymph node involvement. In all patients lung resection with systematic mediastinal and hilar lymph node dissection was performed with curative intent. In N2 lymph node metastases capsules of affected lymph nodes were examined microscopically as to whether extracapsular extension was present. Results: 51 patients (43 %) had extracapsular extension (ENE). Most of these patients (n=35) only had ENE in a single lymph node (69 %). The overall 5-year survival rate was 24.6 % and progression-free survival rate 17.8 %. In the multivariate analysis OS was worse for patients with multiple affected pN2 stations, concurrent N1 metastases, increasing age, and larger tumor size. For the percentage of lymph nodes affected with ENE (of total examined) only a non-significant trend towards worse OS could be observed (p=0.06). Conclusions: Although we could not demonstrate significant prognostic differences between N2 extra capsular nodal involvement within our patient population, other analyses may yield different results. However, clinicians should continue performing thorough lymph nodes dissections in order to achieve local complete resection even in patients with extra capsular tumor spread.

Diffuse Alveolar Hemorrhage Associated with Epithelioid Angiosarcoma of the Lung: A Challenging Diagnosis.

A 68-year-old patient presented with persistent hemoptysis and weight loss. A CT scan showing diffuse bilateral ground-glass opacities and nodules was followed by bronchoscopy. While diffuse alveolar hemorrhage (DAH) could be seen, specimens obtained during bronchoscopy did not provide conclusive histological findings. The decision was made to conduct video-assisted wedge resection, after which histological examinations revealed the diagnosis of bifocal nodular manifestation of an epithelioid angiosarcoma in the lung. Being a rare entity even among sarcomas, these kinds of tumors can be primary lung tissue angiosarcomas or metastatic lesions with primaries in places like the skin, breast, and heart. Treatment usually includes chemotherapy, but prognosis remains grim. This case highlights that in DAH, uncommon causes should be considered, and sufficient probe gathering is the key to early diagnosis and treatment.

Value of 18F FDG-PET/CT parameters on long term follow-up for patients with non-small cell lung cancer.

Objectives: The purpose of this study was to investigate the value of PET/CT in the preoperative staging of non-small cell lung cancer in predicting long-term survival and diagnostic performance, validated by histopathology following surgical resection. Methods: Between 02/2009 and 08/2011, 255 patients with non-small cell lung cancer were included in this single-center prospective study. All underwent 18F FDG-PET/CT for pre-operative staging, and in 243 patients complete surgical resection was possible. Regarding lymph node involvement and extrathoracic metastases, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using the histopathological staging as reference. Median follow-up for censored patients was 9.1 years. Results: Overall 5-year survival rate of all patients was 55.6%, and of patients who had complete surgical resection it was 58.2%. In multivariate analysis of all surgically resected patients lymph node involvement (p=0.029) and age >61 years (p=<0.001) were significant independent prognostic factors. SUVmax and SUVmean cut-offs between SUV 2 and 11, however, were not associated with better or ;worse survival. The PET-CT sensitivity, specificity, positive predictive value and negative predictive value for predicting lymph node involvement were 57, 95, 88, and 76%, respectively. Furthermore, sensitivity, specificity, positive predictive value, and negative predictive value for detecting extrathoracic metastases were 100, 58, 98, and 100%, respectively. Conclusions: In this study, tumor 18F FDG-uptake values did not provide additional prognostic information. Age>61 years and lymph node metastasis were associated with worse long-term survival in surgically resected patients. 18F FDG-PET/CT scans allow for improved patient selection. However, in staging mediastinal lymph nodes, there is a high rate of false positives and false negatives, suggesting that tissue biopsy is still indicated in many cases.

Is Adjuvant Radiochemotherapy Always Mandatory in Patients with Resected N2 Non-Small Cell Lung Cancer?

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), the pathologic union for international cancer control (UICC) stage IIIA is a heterogeneous entity, with different forms of N2-lymph node involvement representing different prognoses. Although a multimodality treatment approach, including surgery, systemic therapy, and/or radiotherapy, is almost always recommended, in this retrospective observational study, we sought to determine whether long-term survival might be possible in selected patients who are treated with complete surgical resection alone. METHODS: Between 2013 and 2018, we retrospectively identified 24 patients with NSCLC (16 men and 8 women), who were found to have pathologic N2-lymph node involvement, and were treated with complete surgical lung resection and systematic mediastinal and hilar lymph node dissection but no neoadjuvant or adjuvant treatment. RESULTS: The most frequent reason (n = 14) for forgoing adjuvant treatment was patient refusal. The mean overall survival (OS) was 34.5 months (interquartile range [IQR]: 15.5-53.5 months). The mean disease-free survival (DFS) was 18 months (IQR: 4.75-46.75 months). We identified five patients who survived at least 5 years without recurrence (21%). In each of these cases, the nodal metastases were restricted to a single level and no extracapsular lymph node involvement were detected. Additionally, worse DFS was associated with pT3/4 (vs. a lower T-stage), as well as microscopic lymphovascular invasion. CONCLUSION: Although the small sample size precludes any definitive conclusions, it was possible to demonstrate that long-term survival without neoadjuvant and adjuvant treatment is possible in some patients if complete tumor and nodal resection is performed.

A Novel Epitope Quality-Based Immune Escape Mechanism Reveals Patient's Suitability for Immune Checkpoint Inhibition.

BACKGROUND: Immune checkpoint inhibition, especially the blockade of PD-1 and PD-L1, has become one of the most thriving therapeutic approaches in modern oncology. Immune evasion caused by altered tumor epitope processing (so-called processing escapes) may be one way to explain immune checkpoint inhibition therapy failure. In the present study, we aim to demonstrate the effects of processing escapes on immunotherapy outcome in NSCLC patients. PATIENTS AND METHODS: Whole exome sequencing data of 400 NSCLC patients (AdC and SCC) were extracted from the TCGA database. The ICB cohort was composed of primary tumor probes from 48 NSCLC patients treated with nivolumab. Mutations were identified by targeted amplicon-based sequencing including hotspots and whole exomes of 22 genes. The effect of mutations on proteasomal processing was evaluated by deep learning methods previously trained on 1260 known MHC-I ligands. Cox regression modelling was used to determine the influence on overall survival. RESULTS: In the TCGA cohort, processing escapes were associated with decreased overall survival (p= 0.0140). In the ICB cohort, patients showing processing escapes in combination with high levels of PD-L1 (n=8/48) also showed significantly decreased overall survival, independently of mutational load or PD-L1 status. CONCLUSION: The concept of altered epitope processing may help to understand immunotherapy failure. Especially when combined with PD-L1 status, this method can be used as a biomarker to identify patients not suitable for immunotherapy.

Prognostic significance of the pattern of pathological N1 lymph node metastases for non-small cell lung cancer.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC) the pathologic lymph node status N1 is a heterogeneous entity, and different forms of lymph node involvement may represent different prognoses. For methodological reasons, the 8th edition of the TNM staging system for NSCLC makes no official changes to the N descriptor. However, there is evidence that different subforms of N1 disease are associated with different prognoses, and it is now recommended that clinicians record the number of affected lymph nodes and nodal stations for further analyses. In this investigation we sought to determine whether patients with different levels and types of N1 lymph node involvement had significantly different 5-year survival rates. METHODS: We retrospectively identified 90 patients with NSCLC (61 men, 29 women), who were treated between 2008 and 2012 and found to have pathologic N1 lymph node involvement and tumor sizes corresponding to T1 or T2. All patients were treated in curative intent with surgical lung resection and systematic mediastinal and hilar lymph node dissection. RESULTS: The overall 5-year survival rate was 56.3%. In the univariate analysis, lower tumor stage and tumor histology other than large-cell carcinoma were significantly associated with better long-term survival. Patients with solitary lymph node metastases also had longer disease-free survival than those with multiple nodal metastases. In the multivariate analysis, large-cell carcinoma and Union for International Cancer Control (UICC) stage IIB were independently associated with worse survival, while pneumonectomy, compared to lobar or sublobar resection, was independently associated with better survival. CONCLUSIONS: Although we did not observe significant prognostic differences between N1 subcategories within our patient population, other analyses may yield different results. Therefore, these data highlight the need for large, well-designed multicenter studies to confirm the clinical significance of N1 subcategories.

A Patient with Non-Hodgkin Lymphoma and Nonspecific Interstitial Pneumonia during Ibrutinib Therapy.

We present a 74-year-old male with nonspecific interstitial pneumonia (NSIP) during treatment with ibrutinib for mantle cell lymphoma. Previously, the patient had received six cycles of bendamustine and rituximab and six cycles of R-CHOP, followed by rituximab maintenance therapy. Respiratory tract complications of ibrutinib other than infectious pneumonia have not been mentioned in larger trials, but individual case reports hinted to a possible association with the development of pneumonitis. In our patient, the onset of alveolitis that progressed towards NSIP together with the onset of ibrutinib treatment suggests causality. One week after ibrutinib was discontinued, nasal symptoms resolved first. A follow-up CT showed a reduction in the reticular hyperdensities and ground-glass opacities, suggestive of restitution of the lung disease. To our knowledge, this is the first case showing a strong link between ibrutinib and interstitial lung disease, strengthening a previous report on subacute pneumonitis. Our findings have clinical implications because pulmonary side effects were reversible at this early stage. We, therefore, suggest close monitoring for respiratory side effects in patients receiving ibrutinib.

Value of thyroid transcription factor (TTF)-1 for diagnosis and prognosis of patients with locally advanced or metastatic small cell lung cancer.

BACKGROUND: The aim of this study was to analyze the frequency of Thyroid Transcription Factor (TTF)-1 expression in small cell lung cancer (SCLC) and its value for the diagnosis of SCLC, the response to first line treatment as well as the prognostic impact on overall survival (OS). METHODS: We analyzed a total of 294 patients (m, n = 184; f, n = 110) with SCLC (stage IIIA, n = 32; IIIB, n = 87; IV, n = 175) diagnosed in our institution between January 2005 and December 2008. Patient's characteristics comprising age, gender, histology and first line treatment were included into the analyses. For the follow-up of patients the governmental death registrar was used. The TTF-1 immunostaining was prospectively performed. CT scans of all patients were reviewed and response to treatment was evaluated using the Response Evaluation Criteria In Solid Tumors 1.0 (RECIST) criteria. RESULTS: A total of 221 of the 294 patients were eligible for analysis. Patients with TTF-1-positive SCLC had a median OS of 374 (95% CI 306-442) days. The OS of patients with TTF1-negative SCLC was 290 (95% CI 191-389) days, which was not significantly shorter (p = 0.254). Also stratification for tumor stage did not reveal significant difference in OS. Analyzing the disease control rate (DCR) in patients with metastatic disease (stage IV), we observed a significantly (p = 0.006) improved response to treatment in the group of patients with TTF-1-expression (DCR 86% vs. 56%). Regarding the overall response rates (ORR) in the entire population, there was no difference observed between both subgroups. (TTF-1-pos. 75.3% vs. TTF-1-neg. 71.4%; p = 0.642). CONCLUSIONS: The diagnostic information of TTF-1 in SCLC seems to be limited. TTF-1 had no prognostic value concerning OS, but may serve as a predictor for response to first line chemotherapy. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5811254651472285.

Diagnostic yield of transbronchial cryobiopsy in non-neoplastic lung disease: a retrospective case series.

BACKGROUND: Due to the small amount of alveolar tissue in transbronchial biopsy (TBB) by forceps, the diagnosis of diffuse, parenchymal lung diseases (DPLD) is inherently problematic, with an overall low yield. The use of cryotechnique in bronchoscopy, including TBB by cryoprobe, has revealed new opportunities in the endoscopical diagnosis of malignant and non-malignant lung diseases. METHODS: To evaluate TBB by cryotechnique for non-neoplastic lung diseases, we analyzed 52 patients (mean age 63 ± 13 years) with unclear DPLD. These individuals underwent bronchoscopy with TBB by cryoprobe. Thereafter histopathological results were compared with the clinically evaluated diagnosis. RESULTS: No major complications were seen. Mean specimen diameter in the histological biopsies was 6.9 ± 4.4 mm (Range 2 - 22 mm). A correlation between clinical and histopathological diagnoses was found in 79% of cases (41/52). In the case of UIP (usual interstitial pneumonia) pattern, the concordance was 10/15 (66%). CONCLUSION: Based on these results TBB by cryotechnique would appear to be a safe and useful method that reveals new perspectives for the endoscopical diagnosis of DPLD.

Morphometrical analysis of transbronchial cryobiopsies.

The recent introduction of bronchoscopically recovered cryobiopsy of lung tissue has opened up new possibilities in the diagnosis of neoplastic and non-neoplastic lung diseases in various aspects. Most notably the morphological diagnosis of peripheral lung biopsies promises to achieve a better yield with a high quality of specimens. To better understand this phenomenon, its diagnostic options and perspectives, this study morphometrically compares 15 cryobiopsies and 18 transbronchial forceps biopsies of peripheral lung tissue a priori without considering clinical hit ratio or integration of results in the clinical diagnostic processing. Cryotechnically harvested specimens were significantly larger (mean: 17.1 ± 10.7 mm2 versus 3.8 ± 4.0 mm2) and contained alveolar tissue more often. If present, the alveolar part in cryobiopsies exceeded the one of forceps biopsies. The alveolar tissue of crybiopsy specimens did not show any artefacts. Based on these results cryotechnique seems to open up new perspectives in bronchoscopic diagnosis of lung disease.