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G. Veronesi
Moderator of
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SC02 - Multifocal Lung Cancer (ID 326)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 4
- Moderators:G. Veronesi, S. Cicenas
- Coordinates: 12/05/2016, 11:00 - 12:30, Strauss 1
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SC02.01 - Multiple Primary Lung Cancers Versus Lung Metastases: Pathological Differential Diagnosis (ID 6604)
11:00 - 11:20 | Author(s): E. Thunnissen
- Abstract
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Abstract:
Introduction The pathological differential diagnosis of in a patient with synchronous multiple tumors has a similar thought process for classic morphology as for DNA analysis. Metachronous multiple lung cancers are not discussed here, as the provided title implies a clinical situation at moment in time. In the end of the text the usefulness of clinical context is mentioned.[1–5] Morphology In the setting of obvious metastatic dissemination, histologic appearance is generally conserved. This implies that most metastases look alike and in most instances also have a similar morphologic appearance as the primary tumor. However, dedifferentiation occasionally occurs in metastases. Thus it is reasonable to conclude that lesions of different histological types, e.g. squamous cell and adenocarcinoma, are two separate primary cancers. Recently, it was suggested that differences in a comprehensive histologic assessment may provide an argument for separate primary cancers. However, resection specimen analysis is required for this assessment, making this approach only useful in about 15-20% of the cases. Moreover, an evidence based data set supporting comprehensive histologic assessment is currently lacking. Reproducibility has to be taken into account.[6] In contrast to different morphological types, in case of two tumors with similar morphology a conclusion for same lineage (primary tumor- metastases relation) or different lineage (two primary tumors) is not easy to reach. The reason for this is that within an individual the genetic predisposition and etiologic factors are the same and may lead to separate tumors with the same morphology, which may still represent two lineages (thus two primary tumors) or alternatively, the same morphology in metastatic setting is one lineage. In case of multiple adenocarcinoma in-situ lesions, they are assumed to be separate primaries. In summary , in comparing two tumors differences in morphologic types is conclusive for second primary tumors, but demonstration of the same morphology is not sufficient for lineage analysis. DNA changes Demonstration of specific driver mutations by widely available PCR sequencing techniques may have use in establishing lineage.[7]In case of different driver mutations between two tumors, this obviously provides a strong argument for two primary (lung) cancers. However the frequency of discordant driver mutations is not so high. Noteworthy is that the demonstration of different passenger mutations does not have any use for lineage determination. In case of equal driver mutations a conclusion about lineage is not easy to reach.[8,9]Not only because the genetic predisposition and etiologic factors are the same, but also because in certain genes hotspot mutations occur. Thus simple demonstration of the same mutation does not provide definite evidence for lineage analysis. On this matter more research is needed with posterior probability analysis involving a relevant number of similar mutations. A detailed genetic assessment such as in comparative genomic hybridisation (CGH) may have greater discriminative power but has been used in only a few small studies.[10]In array CGH the number of data points is orders of magnitude greater than in mutation analysis. Array CGH encompasses the predisposition and etiologic factor related copy number variations (CNV) as well as lineage specific CNV. In this sense comparison of exact breakpoints in gene rearrangements is useful. Although the data are limited as the assessment was in the past complex, nowadays arrayCGH in the form of shallow sequencing can reliable be performed on small biopsies as well. To which extend NGS with a large mutation panel may be useful remains to be seen. In summary , different driver mutations is conclusive for second primary tumors, but demonstration of the same driver mutation is not sufficient for lineage analysis. Clinical context Adding clinical context provides interesting arguments. 1) Imaging may show multiple ground glass opacities (mGGO) and lack of enlarged lymph nodes. Although the morphology may be similar (lepidic pattern with AIS, MIA, Invasive adenocarcinoma) the mGGO lesions are considered to be separate primaries. In case of part solid component the morphological equivalent is usually infarction (=benign) or invasive cancer. 2) Imaging may show multiple consolidations (pneumonic type) with mostly the morphological correlate of invasive mucinous adenocarcinoma. 3) Abundance of nodular lesions, provides an argument for metastases (although rare exceptions exist, e.g. DIPNECH, Carney’s triad), while lack of nodal or systemic metastases provides an argument of two primary lung cancers. 4) Clinical follow-up is in hindsight only partly useful: lack of nodal or systemic metastases provides an argument of two primary lung cancers, while presence of local and/or distant metastases may be due to one of the two or both lung cancers. Conclusion If morphological and/or DNA analysis provides differences between two tumors it is relatively easy to establish that these pulmonary foci of cancer are separate primary tumors. Many commonly used characteristics are associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended. References 1. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J. Thorac. Oncol. 11, 639–50 (2016). 2. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 681–92 (2016). 3. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic-Type of Involvement in the Forthcoming Eighth. J. Thorac. Oncol. 11, 666–680 (2016). 4. Kozower, B. D., Larner, J. M., Detterbeck, F. C. & Jones, D. R. Special treatment issues in non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143, e369S–99S (2013). 5. Detterbeck, F. C. et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 651–65 (2016). 6. Thunnissen, E. et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod. Pathol. 25, 1574–83 (2012). 7. Vignot, S. et al. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J. Clin. Oncol. 31, 2167–72 (2013). 8. Arai, J. et al. Clinical and molecular analysis of synchronous double lung cancers. Lung Cancer 77, 281–7 (2012). 9. de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science (80-. ). 346, 251–256 (2014). 10. Macintyre, G., Ylstra, B. & Brenton, J. D. Sequencing Structural Variants in Cancer for Precision Therapeutics. Trends Genet. 32, 530–42 (2016).
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SC02.02 - Surgical Choices for Patients with Multifocal Lung Cancer (ID 6605)
11:20 - 11:40 | Author(s): S. Swanson
- Abstract
- Presentation
Abstract:
The Surgical Choices for Patients with Multifocal Lung Cancers Surgery for patients with multiple lung lesions is a growing domain. CT scans are obtained frequently and have high resolution such that any lesion in the lung that is 2 millimeters or larger can be identified. Also, it appears that multifocal lung lesions are more common now. At the same time, surgical technique and technology (minimally invasive) have evolved so identifying and resecting small lesions is straightforward and associated with very little morbidity and pain. In most cases there is one lesion (primary lesion) that is more concerning and others that are smaller, less solid or relatively unchanged over time. Often a diagnosis of all of the lesions is not known at the time of surgical intervention and in many cases no diagnosis is known ahead of time. Thus, the surgeon must integrate many factors when operating on multifocal lung findings. What are risk factors that the patient will have lung cancer, what are the patient’s co-morbidities and underlying lung function? When is it important to establish a pre-operative diagnosis? How important is it to resect all of the pulmonary lesions seen on CT scan? Will other therapy be needed? In general, our approach is to obtain a pre-operative diagnosis when possible if the surgery will be particularly challenging based on the location and number of the lesions and/or if the patient has very compromised lung function. The most important point is to anatomically resect the primary lesion; that nodule which is largest, most solid and/or growing the fastest. If the lesion is 2 centimeters or smaller and located within a segment that is straightforward to resect (superior segment lower lobe, lingula or upper division of the left upper lobe, posterior segment of the right upper lobe, medial basilar segment of the lower lobe or composite basilar segments of lower lobe) then a segmentectomy is the procedure of choice. This will provide an excellent oncologic outcome and more readily permit other pulmonary resection than if a lobectomy or greater had been carried out. In all cases a lymph node dissection should be performed and in the case of a sublobar resection it is important to assess, by frozen section, the intersegmental node or nodes between the area being removed and the part of the lobe being left (sump), to be sure no disease remains related to this primary lesion. If the sump node is positive then a lobectomy should be strongly considered. If the lesion is greater than 2 centimeters and for those deep seated more central lesions, a lobectomy is the best operation. If the lesion is about one centimeter and subpleural then a wide wedge resection can be considered though this is an unusual situation for the primary lesion. For the other lesions (non-primary), if they are ipsilateral and easy to identify and resect then they should be removed at the time of the surgery for the primary lesion. If it is possible to resect these lesions with a segment (preferable) or wide wedge this is best. If the non-primary lesions are pure ground glass, relatively small (i.e. less than 2-3 centimeters) and stable then it is reasonable to leave them in place for close follow-up. Once the permanent pathology including molecular analysis is done and the patient has recovered then surgery for the contralateral lesions is considered. Factors that are important in this are residual pulmonary function (repeat pft’s after the first operation), size (both baseline and recent growth) and density of the contralateral lesions. Also, pathology of the resected tumors and whether they represented separate primary tumors or possibly were metastatic tumors, although even with molecular analysis this can be difficult to ascertain, is important in planning. Surgery on the contralateral lesions should be as lung-sparing as possible with segmentectomy being the procedure of choice when possible followed by wide-wedge resections or lobectomy if dictated by size and location. The outcome of patients who had surgery for multiple lung cancers is generally quite good and not statistically different than the outcome for a solitary lung cancer. The patients in these series were highly selected. In most cases the pathology of these lesions is a mix between invasive adenocarcinoma (various subtypes), minimally invasive adenocarcinoma and adenocarcinoma in-situ. Whether mutations are identified is variable and does not seem to influence prognosis. Use of adjuvant therapy depends on the completeness of resection, the nodal status and the molecular analysis of the resected tumors. In general, assuming no nodal involvement and complete resection of the lesions removed, no adjuvant therapy is recommended. In all cases close follow-up is mandatory with visits and frequent ct scans (2-3/yr for 2 years then 1-2/year for 3 years then 1/yr for life). Graph of Survival for patients treated by surgical resection for synchronous primary lung cancers. Figure taken from: Finley et al. Journal of Thoracic Oncology. 2010. (ref 2) Figure 1 References: Shimada et al. Survival of a surgical series of lung cancer patients with synchronousmultiple ground-glass opacities, and the management of the residual lesions. Lung Cancer 2015 Finley et al. Predictors of outcomes after surgical treatment of synchronous primary lung cancers. Journal of Thoracic Oncology. 2010. Bonanno et al. Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman. Lung Cancer 2016. Fonseca A and Detterbeck FC. How many names for a rose: Inconsistent classification of multiple foci of lung cancer due to ambiguous rules. Lung Cancer 2014. Yasuda M et al. How should synchronous multiple primary adenocarcinomas of the lung be resected? Annals of Thoracic Surgery 2014. Wolf AS et al. Lobectomy versus sublobar resection for small (2 cm or less) non-small cell lung cancers. Annals of Thoracic Surgery 2011. Mohiuddin K et al. Relationship between margin distance and local recurrence among patients undergoing wedge resection for small (<2 cm) non-small cell lung cancer. Journal of Thoracic and Cardiovascular Surgery. 2014. Nakata M et al. Surgical treatments for multiple primary adenocarcinoma of the lung. Annals of Thoracic Surgery. 2004. Battafarano RJ et al. Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival. Annals of Thoracic Surgery. 2002. Gu B et al. A dominant adenocarcinoma with multifocal ground glass lesions does not behave as advanced disease. Annals of Thoracic Surgery. 2013.
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SC02.03 - Surgery for Ground Glass Opacity: Sublobar Resection? (ID 6606)
11:40 - 12:00 | Author(s): S. Watanabe
- Abstract
- Presentation
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History of standard surgical procedure for lung cancer In 1933, Graham reported the first successful pneumonectomy for a lung cancer patient, who survived for 18 years after surgery. In 1951, Cahan suggested that pneumonectomy with regional lymph node dissection should be a routine procedure for lung cancer in 1951. Then in 1960, Cahan reported the first 48 cases that successfully underwent lobectomy with regional lymph node dissection, which was called “radical lobectomy.” Since then, this procedure was universally accepted and has remained a standard surgery for lung cancer. As for sublobar resection, segmentectomy was initially used for the resection of localized bronchiectasis as reported by Churchill and Belsey (1939). In 1973, Jensik reported their 15-year successful experience of segmentectomy for lung cancer patients. However, the use of sublobar resection as definitive management of NSCLC has been a controversial issue. Lung Cancer Study Group (LCSG) (1995) conducted the only randomized trial comparing sublobar resection with lobectomy for stage IA NSCLC patients. They observed a 75% increase in recurrence and a 50% increase in cancer death in the patients undergoing sublobar resection, compared to those in the patients undergoing lobectomy. This is the reason why lobectomy has remained a standard lung cancer surgery for a half century since Cahn’s successful report in 1960. However, recently, we encounter many patients with the subsolid nodule、and a certain percentage of those patients are multifocal lesion. The significance and role of sublobar resection for subsolid tumor have become importanat so far. Controversies in sublobar resection for patients with small-sized NSCLC Sublobar resection is a lung parenchyma-preserving surgery with limited nodal dissection. However, even small-sized lung cancer less than 2 cm in size shows hilar and mediastinal nodal disease with an incidence of more than 20%. Although positron emission tomography (PET) is considered to be the most sensitive and accurate investigation for screening of lymph node involvement, with a sensitivity of 79 to 85% and specificity of 90 to 91% in a meta-analysis, the assessment of nodal status by PET is not reliable in patients with microscopic nodal metastasis. Riquet (1989) reported that lung cancer metastasizes so easily to the mediastinum that selection of the patients for limited surgery should be discussed carefully. Furthermore, lung cancer has a phenomenon termed “skip metastasis” consisting of N2 disease without N1 involvement with the incidence of 20-38% in N2 patients. Therefore, lobectomy with hilar and mediastinal lymph node dissection is considered to be a basic standard procedure for lung cancer. Differences in survival between sublobar resection and lobectomy However, with the recent development of the CT scanner, the number of very early-stage lung cancer showing ground-grass opacity (GGO) on CT is rising as well, and a new therapeutic strategy for nodal dissection has been required. Proposals of sublobar resection for small-size lung cancer less than 2 cm have been undertaken in some previous reports. Many retrospective studies of sublobar resection have already been undertaken for stage IA NSCLC patients. Regarding surgery for compromised stage IA patients, Hoffmann (1980), Landreneau (1997) and Campione (2004) showed no significant survival difference between sublobar resection and lobectomy group. Okada (2001) and Koike (2003) conducted the comparative study between intentional sublobar resection and standard lobectomy in patients with tumors 20mm or less in diameter. They showed no significant difference in survival between two groups and suggested that sublobar resection was acceptable operation for small-sized lung cancer. Nakamura (2005) reported the results of meta-analysis of 14 comparative studies showing survival difference between lobectomy and sublobar resection. He showed survival after lobectomy was slightly better at 1, 3, and 5 years, but the differences were not significant. Therefore, lobectomy with mediastinal dissection could be an excessive resection for selected patients with early lesion. Lobectomy, however, still remains to be a standard procedure for most patients with lung cancer, simply because there has been no universally accepted guidelines for conducting sublobar resection in the clinical settings. We should wait the final results of clinical trials shown in the following chapter. Clinical trials regarding sublobar resection vs. lobectomy and future perspective Japan Clinical Oncology Group (JCOG) has conducted a cohort study (JCOG0201) evaluating correlation between radiological and pathological findings in stage I adenocarcinomas. With pathologic non-invasive adenocarcinoma defined as those with no lymph node metastasis or vessel invasion, radiological non-invasive lung adenocarcinoma was defined as those with a consolidated maximum tumour diameter to tumour diameter ratio (C/T ratio) of less than 0.5. Currently, a prospective, randomized, multiinstitutional phase III trial for small-sized (<=2 cm) lung cancer patients is being conducted by Cancer and Leukemia Group B (CALGB140503) to determine the effectiveness of an intentional sublobar resection for small-sized peripheral tumors. Similar phase III study is also being conducted by JCOG (JCOG0802). JCOG has already accumulated planned number of patients and now following the patients. JCOG is also conducting other two prospective multiinstitutional phase II trials regarding the sublobar resection for GGO-dominant type tumors. One is JCOG0802, wide wedge resection or segmentectomy for non-solid GGO lesion less than 2cm, and the other is JCOG1211, segmentectomy for part-solid GGO lesion with less than 50% solid part inside and 2.1-3.0 cm in tumor diameter. Since the clear evidence regarding the survival benefit of sublobar resection for lung cancer patient is lacking so far, lobectomy should be an appropriate therapy for medically operable lung cancer patient at the moment. Abovementioned randomized trials will clearly define the role of sublobar resection in patients with stage I patients. As the number of early-stage peripheral lung cancers is increasing, and a certain number of patients are with multifocal small lesion, the surgical procedure for lung cancer should be tailored to each case by considering CT findings.
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SC02.04 - Interactive Presentation of Clinical Cases with Multifocal Lung Cancer (ID 6607)
12:00 - 12:20 | Author(s): A. Toker
- Abstract
- Presentation
Abstract not provided
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