Alessia Nottegar

Prognostic impact and implications of extracapsular lymph node involvement in colorectal cancer: a systematic review with meta-analysis

BACKGROUND The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor-node-metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer. MATERIALS AND METHODS Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders. RESULTS Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42-2.16, P < 0.0001, I(2) = 60%; HR = 1.69, 95% CI 1.32-2.17, P < 0.0001, I(2) = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65-2.61, P < 0.0001, I(2) = 47%; HR = 2.31, 95% CI 1.54-3.44, P < 0.0001, I(2) = 48%). CONCLUSIONS Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.

True 3q Chromosomal Amplification in Squamous Cell Lung Carcinoma by FISH and aCGH Molecular Analysis: Impact on Targeted Drugs

Squamous lung carcinoma lacks specific “ad hoc” therapies. Amplification of chromosome 3q is the most common genomic aberration and this region harbours genes having role as novel targets for therapeutics. There is no standard definition on how to score and report 3q amplification. False versus true 3q chromosomal amplification in squamous cell lung carcinoma may have tremendous impact on trials involving drugs which target DNA zones mapping on 3q. Forty squamous lung carcinomas were analyzed by FISH to assess chromosome 3q amplification. aCGH was performed as gold-standard to avoid false positive amplifications. Three clustered patterns of fluorescent signals were observed. Eight cases out of 40 (20%) showed ≥8 3q signals. Twenty out of 40 (50%) showed from 3 to 7 signals. The remaining showed two fluorescent signals (30%). When corrected by whole chromosome 3 signals, only cases with ≥8 signals maintained a LSI 3q/CEP3 ratio >2. Only the cases showing 3q amplification by aCGH (+3q25.3−3q27.3) showed ≥8 fluorescent signals at FISH evidencing a 3q/3 ratio >2. The remaining cases showed flat genomic portrait at aCGH on chromosome 3. We concluded that: 1) absolute copy number of 3q chromosomal region may harbour false positive interpretation of 3q amplification in squamous cell carcinoma; 2) a case results truly “amplified for chromosome 3q” when showing ≥8 fluorescent 3q signals; 3) trials involving drugs targeting loci on chromosome 3q in squamous lung carcinoma therapy have to consider false versus true 3q chromosomal amplification.

ALK/EML4 Fusion Gene May Be Found in Pure Squamous Carcinoma of the Lung

Introduction: The report of cases of lung squamous cell cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements raises the question whether this histologic subtype should be also evaluated for such molecular predictive test. Methods: A consecutive series of 40 lung pure squamous cell carcinomas were analyzed for ALK gene status by fluorescence in situ hybridization. Squamous differentiation was validated using an immunohistochemical panel including n-p63 (p40), cytokeratin (CK) 5/6, sex-determining region Y (SRY)-Box2 (SOX2), thyroid transcription factor 1, CK7, and Napsin-A. Results: Squamous differentiation was confirmed in all tumors as they stained positive for n-p63 and CK5/6 and negative for thyroid transcription factor 1 and Napsin-A. One of 40 cases (2.5%) showed an ALK rearrangement on fluorescence in situ hybridization analysis. Conclusions: ALK translocation may be found in lung pure squamous cell carcinomas. Our data suggest the opportunity to test ALK rearrangements on biopsy samples harboring squamous cell cancer differentiation.

Prognostic implications of extranodal extension in node-positive squamous cell carcinoma of the vulva: A systematic review and meta-analysis

Squamous cell carcinoma (SCC) of the vulva is the fourth most common gynecological cancer, usually staged with the TNM or FIGO systems. Since 2009, FIGO staging has taken the extranodal extension (ENE) of lymph node metastases into account. ENE is defined as the spread of a lymph node metastasis into surrounding soft tissue. Although the TNM and FIGO systems acknowledge the importance of ENE in SCC, no comprehensive studies have analyzed the prognostic impact of this parameter. We therefore queried the PubMed and SCOPUS databases from their inception up until 04/01/2015, adopting no language restrictions: all prospective studies reporting on prognostic parameters in patients with vulvar SCC, and comparing participants with and without ENE were eligible for our analysis. Data were summarized using risk ratios (RR) for the number of deaths/recurrences and hazard ratios (HR) for the time-dependent risk related to ENE positivity, adjusting for potential confounders. Among 859 hits, 13 studies were found eligible and were included in our meta-analysis. Compared with ENE-negative (ENE-) cases, the ENE-positive (ENE+) patients had significantly higher rates of all-cause mortality (6 studies: RR = 3.18; 95%CI: 2.02-5.00, p < 0.0001, I(2) = 56%), cancer-specific mortality (3 studies: RR = 2.03; 95%CI: 1.12-3.69, p = 0.02, I(2) = 80%), and recurrence (4 studies: RR = 2.69, 95%CI: 1.61-3.76, p < 0.0001, I(2) = 57%). Using HRs after adjusting for potential confounders, ENE + carried a significantly higher risk of all-cause mortality (6 studies: HR = 3.08, 95%CI: 1.73-5.48, p < 0.0001, I(2) = 66%), and recurrence (5 studies: HR = 3.93, 95%CI: 2.33-6.62, p < 0.0001, I(2) = 28%). Our meta-analysis clarifies the prognostic significance of ENE in vulvar SCC, also pointing to its implications for gross sampling, histology and oncological staging.

FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma

BackgroundLobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed.MethodsFifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases.FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3–6 signals) of the locus specific FGFR-1 gene.ResultsThree (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3–6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals.The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases.Conclusions1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.

Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis

Biallelic inactivation of the tumor suppressor gene BRCA1‐associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1‐) for all‐cause mortality, cancer‐specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1‐ were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time‐dependent risk related to BAP1‐ adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1‐: n = 697; BAP1+: n = 2,750), with a median follow‐up over 60 months, were meta‐analyzed. Compared to BAP1+, BAP1‐ significantly increased all‐cause mortality, cancer‐specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high‐tumor grading (P < 0.0001), and that BAP1 mutated is more common in women than in men (P < 0.0001). In conclusion, on the basis of our meta‐analysis, we have demonstrated a peculiar role of BAP1 in influencing the prognosis in cancer. Thus, BAP1 could be considered as an important potential target for personalized medicine.

Different prognostic roles of tumor suppressor gene BAP1 in cancer

Biallelic inactivation of the tumor suppressor gene BRCA1‐associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1‐) for all‐cause mortality, cancer‐specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1‐ were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time‐dependent risk related to BAP1‐ adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1‐: n = 697; BAP1+: n = 2,750), with a median follow‐up over 60 months, were meta‐analyzed. Compared to BAP1+, BAP1‐ significantly increased all‐cause mortality, cancer‐specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high‐tumor grading (P < 0.0001), and that BAP1 mutated is more common in women than in men (P < 0.0001). In conclusion, on the basis of our meta‐analysis, we have demonstrated a peculiar role of BAP1 in influencing the prognosis in cancer. Thus, BAP1 could be considered as an important potential target for personalized medicine.

Prognostic impact of extra-nodal extension in thyroid cancer: A meta-analysis.

Lymph node involvement is common in thyroid cancer, but the system of staging does not consider the histological features of lymph node metastases. We conducted a meta‐analysis to investigate the prognostic role of extranodal extension (ENE) in thyroid cancer patients.

Extranodal extension in N1-adenocarcinoma of the pancreas and papilla of Vater: a systematic review and meta-analysis of its prognostic significance.

The aim of the study was to investigate the prognostic role of extranodal extension (ENE) of lymph node metastasis in adenocarcinoma of the pancreas (PDAC) and papilla [cancer of the papilla of Vater (CPV)]. A PubMed and SCOPUS search from database inception until 5 January 2015 without language restrictions was conducted. Eligible were prospective studies reporting data on prognostic parameters in individuals with PDAC and/or CPV, comparing participants with the presence of ENE (ENE+) with those with intranodal extension (ENE−). Data were summarized using risk ratios for number of deaths/recurrences and hazard ratios for time-dependent risk related to ENE+, adjusted for potential confounders. ENE was found to be very common in these tumors (up to about 60% in both N1-PDAC and CPV), leading to a significant increased risk for all-cause mortality [risk ratio=1.20; 95% confidence interval (CI): 1.06–1.35, P=0.003, I2=44%; hazard ratio=1.415, 95% CI: 1.215–1.650, P<0.0001, I2=0%] and recurrence of disease (risk ratio=1.20, 95% CI: 1.03–1.40, P=0.02, I2=0%). On the basis of our results, in PDAC and CPV, ENE should be considered mandatorily from the gross sampling and pathology report to the oncologic staging and therapeutic approach.

Extranodal extension is an important prognostic parameter for both colonic and rectal cancer

We thank Qin and Huang [1] for their positive comments on our recent meta-analysis [2], in which we assessed the potential relationship between extranodal extension (ENE) of nodal metastasis and prognostic indexes in colorectal cancer. We found consistent evidence that ENE is associated with mortality and recurrence of disease, across multiple sensitivity analyses [2], which remained robust after adjustment for publication bias. Moreover, we conducted meta-regression analyses to explain the low-moderate heterogeneity we encountered (see supplementary Table S8, available at Annals of Oncology online) in line with best practice. Nonetheless, Qin and Huang [1] have proposed two new subgroup analyses using the same database on geographical location (Europe versus Japan) and site of tumor (colon, rectum, both colon and rectum cancer) to test the robustness of our results. Qin and Huang replicated all of our findings, except from the all-cause mortality in colon cancer [hazard ratio (HR) 1.396, 0.848–2.3] and colon and rectum cancer together (HR 1.513, 0.968–2.365). Although these additional analyses are of potential interest, we respectfully share a number of limitations. First, our initial analyses had low-moderate heterogeneity and our meta-regression analyses already significantly explained large portions of the heterogeneity we encountered. Second, Qin and Huang did not report any heterogeneity metric in their new analyses, so it is unclear to what extent their additional analyses addressed their own primary concern that our paper found low-moderate heterogeneity. Third, Qin and Huang included a limited number of studies in each subgroup (only five studies reported HR estimates: two studies for colon, two for rectum and one regarding colorectal cancer). Indeed, they only included 5 studies out of the 13 considered in our meta-analysis, thus type II error might be a factor in their null findings. Moreover, the P for the interaction for this subgroup analysis is 0.229, suggesting that this factor is not a probable moderator of our findings. Notably, the staging system does not separately consider colon and rectum cancer [2], further justifying our approach. Moreover, the meso-rectal adipose tissue, the main anatomical difference between a surgical specimen of colonic and of rectal cancer, contains very few lymph nodes: also from this point of view (i.e. number of lymph nodes and possible metastasis) colonic and rectal cancer can be studied together. Interestingly, the morphologic aspect most similar to ENE, that is represented by the free tumor deposits in adipose tissue (N1c category), is already considered in TNM staging system for both rectal and colonic cancer. Lastly, in other cancer types ENE appeared as a significant prognostic index [3, 4], and also of importance independently from specific anatomical subdistinction (e.g. carcinoma of pancreas versus of ampulla of Vater) [5]. In conclusion, we partly agree with the analyses of Qin and Huang and are grateful that they echo our calls for further research considering the prognostic role of ENE in colorectal cancer. However, we have a number of potential concerns that do not shift our stance, based on the data, that future research should consider colon and rectum cancer as only one entity.