Maria Cristina Bruna

Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms.

BACKGROUND Tumor-infiltrating lymphocytes (TIL) are considered important in anticancer immunosurveillance, although their role has not been clearly established yet. We examined prevalence, correlations, and prognostic significance of TIL among our patient population of resected lung neoplasms. METHODS From 1993 to 2006, the presence of TIL was retrospectively evaluated in 1,290 patients operated on for primary lung neoplasms. Tumor-infiltrating lymphocytes were defined as those intraepithelial lymphocytes located within the cancer cell nests. RESULTS Tumor-infiltrating lymphocytes were detected in 294 patients (23%). A significant difference was found between prevalence in non-small cell lung carcinomas versus neuroendocrine tumors (290 of 1,208, 24% versus 4 of 82, 5%; p = 0.0001). Prevalence was similar in adenocarcinomas, squamous-cell carcinomas, and large-cell anaplastic carcinomas. Logistic regression analysis indicates that TIL correlate with grading (odds ratio, 1.27; 95% confidence interval, 1.04 to 1.55; p = 0.02), tumor dimension (odds ratio, 0.86; 95% confidence interval, 0.79 to 0.94; p = 0.0008), and vascular invasion (odds ratio, 1.62; 95% confidence interval, 1.21 to 2.16; p = 0.0009). A not significantly better survival in the presence of TIL was observed overall (p = 0.20), becoming significant in squamous-cell carcinomas (p = 0.03). In patients with stage I disease, TIL is associated with a significant survival advantage in squamous-cell carcinomas (p = 0.03). The survival advantage increases with the duration of follow-up and is more evident after 4 to 6 years. CONCLUSIONS Tumor-infiltrating lymphocytes are observed in about one fourth of resected lung neoplasms: they are rare in neuroendocrine tumors. Tumor-infiltrating lymphocytes are more frequent in poorly differentiated tumors and in tumors with microscopic vascular invasion. The presence of TIL correlates with an improved survival in squamous cell carcinomas, particularly at early stage. The survival advantage increases with the duration of follow-up.

Significance of the presence of microscopic vascular invasion after complete resection of Stage I-II pT1-T2N0 non-small cell lung cancer and its relation with T-Size categories: did the 2009 7th edition of the TNM staging system miss something?

Introduction: The aim of this study was to assess the significance of microscopic vascular invasion (MVI) in a population of resected patients with early-stage non-small cell lung cancer (NSCLC), along with an analysis of the effect of the combination of MVI and tumor size for the T-size categories T1a-T2b according to the 2009 7th edition of the tumor, node, metastasis (TNM) classification. Methods: From January 1993 to August 2008, 746 patients with pT1-T2N0 NSCLC received resection at our institution. MVI was ascertained using histopathological and immunohistochemical techniques. Results: MVI was observed in 257 patients (34%). Prevalence was higher in adenocarcinoma (ADK) than in squamous cell carcinoma (p = 0.002). A significant correlation was found between MVI and ADK (p = 0.03), increased tumor dimension (p = 0.05), and the presence of tumor-infiltrating lymphocytes (p = 0.02). The presence of MVI was associated with a reduced 5-year survival overall (p = 0.003) and in ADK (p = 0.0002). In a multivariate survival analysis, MVI was an indicator of poor survival overall (p = 0.003) and in ADK (p = 0.0005). In each T category (T1a-T2b) of the 2009 TNM staging system, survival of MVI+ patients was significantly lower than the corresponding MVI− patients; T1a and T1b MVI+ patients had a survival similar to MVI− T2 patients. Conclusions: The finding of MVI in pT1-T2N0 NSCLC is frequent. MVI correlates with adenocarcinoma histotype, increased tumor dimensions, and tumor-infiltrating lymphocytes. The presence of MVI is an independent negative prognostic factor. In our experience, MVI was a stronger prognostic indicator than T size in T1a-T2b categories according to the 2009 TNM staging system.

Adenosquamous lung carcinomas: A histologic subtype with poor prognosis

INTRODUCTION The aim of this study is to evaluate the prognostic factors and outcome of patients operated for adenosquamous (ADS) carcinoma of the lung, in comparison with adenocarcinoma (AD) and squamous cell carcinoma (SCC). METHODS a retrospective review of our thoracic cancer surgical database for patients operated for ADS, SCC and AD between January, 1995 and December, 2009 was done. RESULTS Forty-eight patients (39 males, 81.3%) had ADS; complete tumor resection and lymphadenectomy was accomplished in all patients. A higher stage at presentation was observed in ADS, as compared to AD or SCC (p=0.0001). Three and 5-year survival rates were 25% and 15%. ADS overall survival was worse than AD or SCC (p=0.0005). Three and 5-year survival rates of ADS Stage I were similar to those of Stage IIIA AD or SCC. More than half ADS patients developed distant metastases (MTS) or local recurrences. Brain MTS were the most frequent. Median survival for those patients was 8±2.3 months. Postoperative platinum-based chemotherapy statistically improved patients survival (p=0.02). In the multivariate analysis, the presence of MTS (p=0.001), the tumor perineural invasion (p=0.01) and the tumor stage (p=0.0005) were factors associated with poor prognosis. Adjuvant chemotherapy was a significant positive prognostic factor (p=0.00001). CONCLUSIONS ADS are uncommon and extremely aggressive lung tumors. Adjuvant chemotherapy should be administered even in Stage I radically resected tumors. A whole brain postoperative prophylactic radiotherapy could be proposed to reduce risk of developing brain MTS.

Thymoma: inter-relationships among World Health Organization histology, Masaoka staging and myasthenia gravis and their independent prognostic significance: a single-centre experience §

OBJECTIVE In thymomas, World Health Organization (WHO) histology, Masaoka stage and myasthenia gravis (MG) have long been considered important for patient management and outcome. Their role has been independently investigated in the past. Few studies, however, focussed on the correlations among these variables. The aim of the present study was to retrospectively evaluate, in our patient population of resected thymomas, the inter-relationships among MG, WHO histology and Masaoka stage, and to look at how and to what extent one variable is associated with the other two in terms of clinical presentation and survival. METHODS From January 1990 to October 2008, 255 patients received resection of thymoma. MG was present in 105 cases (41%). Histology by WHO was: 25 A (10%), 72 AB (28%), 65 B1 (25%), 69 B2 (27%) and 24 B (9%). Masaoka staging was stage I, 54 cases (21%), stage II, 86(34%), stage III 79 (31%), and stage IVA 36 (14%). Ordinal and logistic regression models were undertaken to analyse correlations among ordinal (WHO histology and Masaoka stage) and categorical (MG, A vs B WHO types) variables. Univariate and multivariate survival analysis were also performed using the same covariates. Overall survival (OS) and disease-free survival (DFS) were calculated. RESULTS MG was associated with early Masaoka stages (odds ratio (OR) 0.45, 95% confidence interval (CI) 0.33-0.62) and B-type thymomas (OR 1.59, 95% CI 1.23-2.05). B-type thymomas were associated with high Masaoka stage (OR 0.46, 95% CI 0.36-0.60). High Masaoka stage was associated with non-MG (OR 3.27; 95% CI 2.00-5.34). In univariate survival analysis, MG (p = 0.01) and Masaoka stage (p = 0.0001) were significant prognostic indicators using OS. Using DFS, WHO histology (A/AB vs B1/B2/B3 types) (p = 0.05) and Masaoka stage (p = 0.0001) had a prognostic significance. In multivariate analysis, only Masaoka stage was an independent prognostic covariate using OS (hazard ratio (HR) 2.57, 95% CI 1.46-4.52, p = 0.001) and DFS (HR 3.18, 95% CI 1.56-6.52, p = 0.001). CONCLUSIONS In thymomas, MG, WHO histology and Masaoka stage are inter-related. MG has an influence on histology and stage at presentation, while two clinical/histologic patterns are more likely: early Masaoka stage A/AB WHO type and high Masaoka stage/B WHO type. Among the three factors, only Masaoka stage had a prognostic significance on OS and DFS. Our results suggest that a consistent staging system for thymomas should take into account all three variables.

Recommended changes for T and N descriptors proposed by the International Association for the Study of Lung Cancer — Lung Cancer Staging Project: a validation study from a single-centre experience

OBJECTIVE The International Association for the Study of Lung Cancer (IASLC) recently recommended changes for T and N descriptors for the next TNM (Tumour, Node, Metastasis) edition. We re-classify our operated patients to evaluate the effectiveness of the IASLC suggestions. METHODS IASLC proposals include: (1) a subdivision of T1 into T1a (< or =2 cm) and T1b (2-3 cm); (2) a subdivision of T2 into T2a (3-5 cm) and T2b (5-7 cm); (3) a re-assignment of T2 >7 cm to T3; (4) a re-assignment of intrapulmonary metastasis in the primary lobe (PM1) and in ipsilateral different lobes (PM2) from T4 to T3 and from M1 to T4, respectively; and (5) a classification of N descriptor by the number of involved lymph node zones into: N0; single-zone N1 (N1a); multiple-zone N1/single-zone N2 (N1b/N2a) and multiple-zone N2 (N2b). From 1994 to 2007, 1805 patients were operated on for non-small-cell lung carcinoma (NSCLC); survival analysis was performed using Cox proportional hazard model to assess the prognostic significance of the T and N descriptors. RESULTS Stratification by T descriptor was: T1a (362 patients), T1b (286), T2a (536), T2b (154), T2 >7 cm (58), T3 (243), PM1 (50) and PM2 (36). Stratification by N descriptor was: N0 (1150 patients), N1a (289), N1b/N2a (200) and N2b (67). A significant survival difference was found between T1a and T1b (hazard ratio (HR) 1.45, 95% confidence interval (CI): 1.10-1.90, p=0.006) but not between T2a and T2b (HR: 1.11, 95% CI: 0.86-1.43, p=0.38). Tumours >7 cm and PM1 had a survival similar to other T3 tumours (HR: 1.05, 95% CI: 0.97-1.14, p=0.2 and HR: 0.99, 95% CI: 0.81-1.21, p=0.94). An excellent patient stratification was provided with the proposed four-category nodal grouping, with significant survival differences between N0 and N1a (HR: 1.81, 95% CI: 1.50-2.21, p=0.0000001), N1a and N1b/N2a (HR: 1.54, 95% CI: 1.21-2.00, p=0.02) and between N1b/N2a and N2b (HR: 1.61, 95% CI: 1.14-2.27, p=0.02). CONCLUSIONS Our experience confirms the IASLC recommendations to subdivide patients by tumour size at 2, 3 and 7 cm, to re-assign PM1 tumours to T3 and to group patients according to the number of involved lymph nodal zones are valid and provide excellent survival stratification.

Pulmonary Metastasectomy for Melanoma

After primary tumor treatment, 30% of patients with malignant melanoma develop metastatic disease, usually associated with a poor prognosis. Effective chemotherapeutic regimens for metastatic melanoma are not currently available. Surgical treatment of pulmonary metastases remains controversial because of the dismal survival rates reported in several studies. However, for patients with good performance status, long disease-free interval, limited metastatic disease, and less aggressive tumor biology, it remains an option. The authors have analyzed their experience in 26 patients operated on between 2000 and 2008 alongside a review of the large series in the literature.

Surgery of colorectal cancer lung metastases: analysis of survival, recurrence and re-surgery

BACKGROUND Surgery is considered an effective therapeutic option for patients with lung metastasis (MTS) of colorectal cancer (CRC). The purpose of the study was to evaluate efficacy and feasibility of lung metastasectomy in CRC patients and to explore factors of prognostic relevance. METHODS This is a retrospective study of patients operated for lung MTS of CRC from 2004 to 2012 in a single Institution. Overall survival (OS) was the primary endpoint. Secondary endpoints were progression free survival (PFS) in resection status R0 and OS in in patients submitted to re-resections. In order to evaluate prognostic factors, a multivariable Cox proportional hazard model was performed. RESULTS One-hundred eighty-eight consecutive patients were included in the final analysis. The median follow-up (FU) was 45 months. The 5-year OS and PFS were 53% (95% CI: 44-60%) and 33% (95% CI: 25-42%), respectively. Two- and 5-year survival after re-resection were 79% (95% CI: 63-89%) and 49% (95% CI: 31-65%), respectively. Multivariate adjusted analysis showed that primary CRC pathological TNM stages (P=0.019), number of resected MTS ≥5 (P=0.009) and lymph nodal involvement (P<0.0001) are independent predictors of poor prognosis. CONCLUSIONS Patients operated and re-operated for lung MTS from CRC cancers showed encouraging survival rates. Our results indicated that primary CRC stage, number of MTS and lymph nodal involvement are strong predictive factors. Prognosis after surgery remained comforting up to four resected MTS. Adjuvant chemotherapy seems to have a benefit on survival in patients affected by multiple metastases. Finally, according to the high rate of unidentified lymph node involvement in pre-operative setting, lymph node sampling should be advisable for a correct staging.

Extended transcervical thymectomy with partial upper sternotomy: results in non-thymomatous patients with myasthenia gravis

OBJECTIVES Thymectomy is a recognized treatment for myasthenia gravis (MG), but the optimal surgical approach is yet to be determined. This study analysed the results in non-thymomatous MG patients treated at our institution using an extended transcervical access with partial upper sternotomy (TC-US), in order to describe cumulative incidence of remission and its predictors. METHODS In the period 1988-2012, 215 non-thymomatous MG patients underwent thymectomy using the TC-US approach. There were 61 males and 154 females (median age: 33 years). Primary end points were complete stable remission (CSR) and pharmacological remission (PR). Clinico-pathological predictors of CSR/PR were analysed including age, gender, preoperative MG symptom duration, preoperative immunosuppression therapy and disease severity. RESULTS The median follow-up period was 127 months. The median preoperative duration of MG symptoms was 9 months (interquartile range 4-13). The median operative time was 65 min (range: 45-135). There was no postoperative death. Morbidity rate was 7% (14 patients, no major complication). Ten patients died at the follow-up (3 of MG). MG symptoms improved in 85% (150/176) of the patients. CSR rate was 34%, PR rate was 4%. Cumulative incidence of CSR/PR was 27, 37 and 46% at 5, 10 and 15 years, respectively. Independent predictors of increased CSR/PR rate were age (P = 0.028) and MG symptom duration <6 months (P = 0.013). CONCLUSIONS Our data suggest that in patients with non-thymomatous MG, thymectomy by TC-US has a remission rate not inferior to those reported after trans-sternal or video-assisted thoracic surgery techniques. The short duration of MG symptoms before thymectomy is a predictor of remission. The technique strikes a reasonable balance between the extent of thymic resection, operative and anaesthesia time, patient acceptance, neurological outcome and costs.

Segmental tracheal resection for invasive differentiated thyroid carcinoma. Our experience in eight cases

PurposeIn differentiated thyroid carcinoma (DTC), complete resection of local disease provides the longest survival and the best palliation. In pursuit of this goal, segmental tracheal or laryngotracheal resection can be performed on patients with DTC invading the airway. The study summarizes the technical aspects of the intervention and analyzes its results in eight patients.MethodsThe results of eight tracheal or laryngotracheal resections for DTC invading the airway were analyzed. Three patients presented with local recurrent disease, whereas five underwent airway resection at the time of thyroidectomy or shortly after. All received a circumferential sleeve resection of the trachea (2–4 tracheal rings) that in three cases extended to the cricoid, followed by end-to-end anastomosis.ResultsPathologic evaluation identified seven papillary and one poorly differentiated carcinomas. No postoperative deaths occurred; one patient required surgical reexploration because of postoperative bleeding, and two air leaks resolved with conservative treatment. Functional results were excellent. During follow-up, one patient died of lung and bone metastases, while in two cases locally persistent/recurrent disease has been detected; two patients are currently free of disease, and in the last three cases only persistent thyroglobulin levels are indicative of residual disease.ConclusionsIn our experience, segmental airway resection is safe, provides excellent functional results, and can warrant adequate control of local disease.

Surgical Treatment of Pulmonary Metastases from Melanoma: Emerging Options

Malignant melanoma (MM) is rapidly becoming a major health problem in the USA and in Europe. It has been estimated that more than 55,000 Americans developed MM in 2004, and that about 8,000 ultimately died of it (1). More than one third of patients operated for MM develop tumor recurrence; melanoma patients’ annual risk of death in Stage IV of the American Joint Committee on Cancer (AJCC) has been estimated to be about 20% during the first 3 years (2). The site of relapse is a very important predictor of survival. Regional lymph node recurrences in fact, may be surgically resected and 5-year survival rate have been reported to be between 20% and 50% (3-4). Distant metastases (MTS), both in visceral and non-visceral sites, reported a 5-year survival of approximately 5% (5-7); for these patients surgery is not often feasible and systemic treatment (chemotherapy, immunotherapy, radiotherapy) is sometimes the curative option. Lung is the second most common site for metastatic MM spread (8). The annual probability of developing lung MTS progressively increases from 10% at 5 years to 17% at 15 years after the resection of the primary tumor (9). Lung MTS are usually asymptomatic, sometimes multiple, occasionally detected with radiological imaging during patient follow-up. Once lung MTS has developed, the possible surgical treatment remains controversial. Even if a clear clinical advantage in overall survival (OS) after resection of pulmonary MTS from osteogenic sarcoma, soft tissue sarcoma, non-seminomatous testicular neoplasms, colorectal and renal cell carcinoma has been demonstrated, 5-year survival rates in melanoma patients were lower, ranging between 5% and 31% (10-12). These ranges indicate how a preoperative patient selection is mandatory. In fact, only 10-35% of all metastatic melanoma patients are suitable for a complete surgical resection (13). Systemic treatments including chemotherapy, radiotherapy, immunotherapy and more recently molecular target agents, demonstrated a partial clinical response only, with severe adverse effect and a dramatic impact on patient’s quality of life (QOL), providing little, if any, attested survival benefit. Chemotherapy regimens may include: dacarbazine, cisplatin and carmusine, alone or in combination with a variety of immunotherapies, including cytokines, monoclonal antibodies and vaccination strategies with synthetic peptides, naked DNA, dendritic cells and recombinant viruses (14-17). Unfortunately, results are presently