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P. Cagle

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    ED 09 - Tissue Is the Issue: Improving Diagnostic Yield in the Age of Minimally Invasive Procedures (ID 9)

    • Event: WCLC 2015
    • Type: Education Session
    • Track: Community Practice
    • Presentations: 4
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      ED09.01 - Optimal Biopsy, Challenges (ID 1806)

      14:15 - 15:45  |  Author(s): S. Dacic

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The majority of patients with lung cancer present in advanced stages, and small biopsy and cytology specimens most frequently provide the only tumor material for diagnosis. Furthermore, the same sample is also needed for molecular studies that guide treatment and management. Lung carcinomas often are diagnosed by minimally invasive techniques and specimens are obtained by bronchoscopic or transthoracic approaches. The choice of the procedure depends on the location, accessibility of the mass and other clinical parameters. Since most adenocarcinomas are peripherally located, the transthoracic approach is often chosen to provide diagnostic samples. Squamous cell carcinoma is most frequently centrally located and the bronchoscopic approach is more common. If cytology specimens, including pleural fluids, are obtained, cell blocks should be prepared. Despite the best efforts, the lesional tissue or the most representative area of the tumor may not be obtained in some cases due to sampling issues. Even when the tumor is sampled, poor tumor differentiation or insufficient characteristic morphological features in the tumor sample will cause the difficulty in rendering a specific diagnosis and would prompt pathologists to use immunohistochemistry. Use of immunohistochemistry greatly reduced the number of lung carcinoma cases classified as non-small cell carcinoma, NOS to only 3%. .In addition to immunohistochemistry, cytology samples should be interpreted in conjunction with histology of small biopsies whenever possible. Immunohistochemistry should be limited only to cases when classification is uncertain and every effort should be made to preserve as much material as possible for molecular studies. There are few strategies besides limited immunohistochemistry panels how this could be accomplished. One approach is to cut unstained slides from a paraffin block after initial hematoxylin-eosin stain sections were obtained. It is essential that histology technicians limit facing of the block and place only one tissue section per slide. Another approach is to have each core biopsy tissue fragment placed into separate blocks during specimen processing so only one block can be used for immunohistochemistry and all of the blocks can be used for molecular studies. Same laboratories in order to avoid tumor microdissection from the unstained slides prefer to core paraffin blocks by 1-mm needles after diagnostic work up. Formalin-fixed, paraffin-embedded tissue samples and cytology aspirates can be used for various testing platforms including next generation sequencing. Each molecular laboratory should establish criteria for specimen adequacy for molecular studies taking into account the specific testing platforms, while surgical pathologists should assess the specimen adequacy. Although PCR-based methods can detect mutations from a single cell, a low copy number DNA template can generate sequence artifacts leading to false results. Therefore, the assessment of adequacy is essential to avoid assays failures and false positive/negative results. Estimates of tumor content from H&E stained sections vary between pathologists and there is no true standard. Acceptable specimens should have a sufficient amount of tumor cells, but also a small proportion of admixed non-neoplastic cells, and no necrosis.[116] If the specimen is inadequate, a new specimen needs to be procured although in this situation decision regarding specimen type is often difficult and depends on many factors including the patient’s health. Alternate non-invasive highly sensitive methods so called “liquid biopsies” have been developed to detect the presence of cancer specific mutations in circulating DNA in blood samples. This approach may result in significant changes in the management of lung cancer patients and may replace invasive procedures. Until then, it is essential that each institution develops its own strategy that addresses the collection and processing of lung cancer samples. At the same time, pathology departments must implement the procedures that would precisely define how to spare the tumor tissue for molecular testing, and how to provide clinically acceptable turnaround time for molecular testing results. It is also essential to define how to integrate diagnostic interpretation and molecular results in a single pathology report. References: Travis WD et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 2013; 137(5):668-84. Lindeman NI. et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from CAP/IASLC/AMP. J Thorac Oncol 2013:8(7):823-59. Francis G, Stein S.Circulating cell-free tumor DNA in the management of cancer. Int J Mol Sci. 2015;1 (6):14122-42

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      ED09.02 - Difficulties Coordinating Care (ID 1807)

      14:15 - 15:45  |  Author(s): R.U. Osarogiagbon

      • Abstract
      • Presentation

      Abstract:
      With 1.6 million new diagnoses and 1.4 million annual deaths worldwide, 230,000 annual cases and 160,000 deaths in the US, lung cancer is the oncologic scourge of the present age. It accounts for 23% of worldwide, and 28% of US, cancer deaths.1 Four decades of advances in diagnostic and treatment modalities, including the current ‘molecular’ decade of rapid-fire discovery of breakthrough therapeutics, have seen aggregate US 5-year survival improve from 12% to 17%.2 Although the deployment of effective population-based tobacco cessation and lung cancer screening programs can change these statistics, there remains the danger of blunted impact because of relatively little progress in the coordination of care, and major deficits in the use of curative-intent therapy. Lung cancer care is complicated. The disease is common and lethal; the primary at-risk population is ravaged by cumulative age- and tobacco-related comorbidities; the lungs and mediastinum are relatively inaccessible; multiple approaches and techniques for diagnosis, staging, and treatment exist, each requires different, highly-trained specialists (radiologists, pulmonologists, surgeons, medical oncologists, radiation oncologists, pathologists, palliative care specialists), using high-cost equipment, to perform high-risk procedures, any one of which may or may not be needed for specific patients. Determining which specific specialists and management approaches are needed for individual patients requires objective evaluation and careful coordination, in order to tailor management to patient needs. Prevailing nihilism about lung cancer care further complicates matters: ‘statistics suggest the patient will die anyway, so what’s the point?’, ‘he brought this on himself by smoking, whose problem is this?’ Care delivery must be better coordinated before we can achieve meaningful improvement in population-level survival statistics. All lung cancer care begins with an abnormal chest x-ray or CT scan. From then, it flows through certain ‘nodal points’: histologic confirmation, radiologic staging, histologic staging, selection of treatment, and (ultimately) outcomes. Each nodal point includes a myriad of options. Diagnosis is usually made by percutaneous (interventional radiologist), bronchoscopic (pulmonologist), or surgical (thoracic surgeon) biopsy ; radiologic staging often involves a PET/CT scan (nuclear radiologist), and brain MRI scan (neuro-radiologist); histologic staging requires an invasive biopsy procedure, which can be transbronchial needle biopsy during conventional bronchoscopy, endobronchial ultrasound-guided (EBUS) biopsy (pulmonologist), endoscopic ultrasound-guided (EUS) biopsy (gastroenterologist), percutaneous image-guided biopsy of a distant stage-defining lesion (interventional radiologist), mediastinoscopy, or other approaches to various parts of the mediastinum (surgeon). Treatment increasingly requires combinations of surgery, radiation therapy, chemotherapy and palliative care. Therefore lung cancer care demands a high degree of coordination. Major, well-described geographic, socio-economic, racial, and age-based disparities in diagnosis, staging, treatment, and outcomes suggest that healthcare systems fail to provide the required level of care coordination. The proportion of patients who make it to surgery, the most important curative treatment modality, varies from 9% in the UK, to 29% in the US.3 Use of invasive staging tests and surgical resection is significantly lower in African Americans than in Caucasians.4,5 Elderly patients are less likely to receive chemotherapy than younger patients.6 Although partly driven by patient choice, improvement in care coordination narrows or eliminates most disparities.7,8 Beyond disparities, access to high-quality care is generally low. ‘Trimodality’ staging (CT, PET/CT scan and invasive staging in combination) although associated with a 2-fold survival improvement was used in only 5% of US patients.9 In a high lung cancer mortality zone of the US, only 17% of curative-intent resections were preceded by invasive staging, including only one-third of patients with clinical N1, N2 or N3 disease (Osarogiagbon, unpublished data). Low rate of histologic confirmation of stage-defining lesions raises the danger of overuse and underuse of treatment modalities. At the extremes are primary surgical resection for patients with clinically evident mediastinal nodal disease, and palliative systemic chemotherapy for patients with false-positive radiologic staging tests or multiple primary cancers erroneously classified as stage IV. Avoiding misuse of diagnostic and staging modalities is equally difficult. The need to recognize and correctly act on non-diagnostic, false-negative and false-positive test results is great. Lung cancer care is often delayed when insufficient-quality diagnostic material or sampling error leads to erroneous reassurance that a high-risk radiologic lesion is benign. The problem is even greater in the use of invasive staging tests. More than half of US mediastinoscopy procedures fail to deliver lymph node tissue for pathology examination.10 This dismal statistic is probably worse with EBUS and EUS. The need for high-quality tissue rises as prognostic and response-predictive implications steadily increase our need for clear histologic categorization (and sub –categorization), and with the advent of molecular prognostication and treatment selection. The demand for high-quality tissue spans the stage spectrum. Therapeutic clinical trials now routinely demand tissue for molecular testing, surgical resection trials increasingly mandate a minimum quality of nodal staging. Patients’ eligibility for clinical trials and our ability to accelerate testing and deployment of novel treatments increasingly hinge on tissue procurement. Pathologists and interventionists who procure tissue must work collaboratively to increase tissue yield for the numerous purposes of treating clinicians. This must be achieved while maintaining patient safety and convenience. The countervailing forces of increasing adoption of minimally invasive diagnostic, staging and treatment modalities and ravenous hunger for high-quality tissue for prognostication and treatment selection collide within individual patients and healthcare systems. Only better coordination, involving all relevant clinicians in early strategic decision-making for each individual patient can prevent the delays, anxieties, exposure to harm, missed opportunity for better treatment outcomes, and looming medico-legal risk that the status quo in lung cancer care represents. Rising survival rates will only increase this conflict, as the need for re-characterization of disease rises, and lung cancer care evolves from a game of checkers to a chess match. REFERENCES 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. 2. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed May 28, 2015. 3. Moghissi K, Connolly CK. Resection rates in lung cancer patients. Eur Respir J 1996;9:5-6. 4. Bach PB, Cramer LD, Warren JL, Begg CB. Racial differences in the treatment of early-stage lung cancer. N Engl J Med 1999;341:1198-205. 5. Lathan CS, Neville BA, Earle CC. The effect of race on invasive staging and surgery in non-small-cell lung cancer. J Clin Oncol 2006;24:413-418. 6. Earle CC, Venditti LN, Neumann PJ, et al. Who gets chemotherapy for metastatic lung cancer? CHEST 2000;117;1239-1246. 7. Laroche C, Wells F, Coulden R, et al. Improving surgical resection rate in lung cancer. Thorax 1998;53:445-449. 8. Brawley OW. Lung cancer and race: equal treatment yields equal outcome among equal patients, but there is no equal treatment. J Clin Oncol 2006;24:332-333. 9. Farjah F, Flum DR, Ramsey SD, et al. Multi-modality mediastinal staging for lung cancer among Medicare beneficiaries. J Thorac Oncol 2009;4:355-363. 10. Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg 2005;80:2051-6.

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      ED09.03 - What Do You Do with Tissue Once Collected? What Tests Are Useful? (ID 1808)

      14:15 - 15:45  |  Author(s): M. Varella-Garcia

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ED09.04 - Prioritization of Tissue Use (ID 1809)

      14:15 - 15:45  |  Author(s): T. Hensing

      • Abstract
      • Presentation

      Abstract:
      The personalized treatment of lung cancer begins with an accurate histologic diagnosis. Lung cancer is a heterogeneous disease and recent advances in understanding the genetic underpinnings of cancer coupled with the development of targeted therapeutics have added to the complexity of the diagnostic evaluation. The previous simple division of lung cancer into small cell and non-small cell histology is no longer adequate, and evaluation of tumors for specific genetic changes and their expression is essential for the precise and accurate diagnoses required for optimal treatment and patient management. In 2011, the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) published a new pathological classification of lung adenocarcinoma.[1] This new system established uniform terminology and diagnostic criteria for both resection specimens and small biopsies. Based on advances in the understanding of lung tumor biology, the correlation between specific tumor histology and outcomes with selected chemotherapy agents, as well as the successful development of novel targeted therapies, this new classification system emphasized the importance of a multidisciplinary approach to the diagnosis of lung cancer in order to best guide management decisions. In the IASLC/ATS/ERS system, several changes to pathological classification of adenocarcinoma were proposed.[1] The term “BAC” (bronchioloalveolar carcinoma) was discontinued and new pathological subtypes were added, including adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. For patients with invasive adenocarcinoma, the new system proposed comprehensive histological subtyping with classification based on predominant histological pattern (lepidic, acinar, papillary, micropapillary and solid). Mucinous tumors were classified as mucinous AIS, mucinous MIA or invasive mucinous adenocarcinoma based on extent of invasion. In subsequent validation studies, pathological subtyping using the IASLC/ATS/ERS adenocarcinoma classification system has been demonstrated to have both prognostic and predictive significance.[2, 3] Patients with AIS and MIA have close to 100% disease-free survival. In contrast, invasive adenocarcinomas with solid and micropapillary predominant histological subtypes were associated with worse overall survival.[2, 4] Because most patients with lung cancer will be diagnosed with advanced-stage disease, one of the most important distinctions between the 2011 IASLC/ATS/ERS classification system and the previous 2004 World Health Association (WHO) classification is the establishment of diagnostic criteria for small biopsies and cytology. Although the focus was on adenocarcinoma, diagnostic criteria for other histologies were also included with the primary focus on distinguishing between squamous cell carcinoma and adenocarcinoma. A limited diagnostic work up was recommended to preserve as much tissue as possible for molecular testing. In cases where the diagnosis can be established based on light microscopy alone, the WHO classification criteria were maintained and no additional confirmatory testing was recommended. In tumors without definite squamous or adenocarcinoma morphology, limited immunohistochemistry may be used to refine the diagnosis. Most tumors can be classified using a single adenocarcinoma marker (i.e. TTF-1 or mucin) and a single squamous marker (i.e. p40 or p63.[5] The acknowledgement that one needs to “preserve as much tissue as possible” for biomarker testing reflects the changing uncertainty in which biomarkers need to be assessed and what techniques might be available for testing. With the identification and validation of actionable molecular targets that can guide therapy in patients with advanced adenocarcinoma, institutions are encouraged to develop consistent strategies for obtaining and managing tissue samples that are optimized for molecular testing. Because this approach has not been validated for squamous histology, tumors with equivocal morphology or IHC findings should be classified as NSCLC-NOS so as not to exclude patients from histology-specific chemotherapy or molecular testing. In 2013, the College of American Pathologists (CAP), IASLC and Association for Molecular Pathology (AMP) published a molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors that included 37 recommendations addressing 5 principal questions, including: (1) When should molecular testing be performed? (2) How should EGFR testing be performed? (3) How should ALK testing be performed? (4) Should other genes be routinely tested in lung adenocarcinoma? And, (5) How should molecular testing be implemented and operationalized?[6, 7] In addition to EGFR and ALK, a number of other molecular alterations have been described that are potentially treatable with targeted agents. Because the data were insufficient to support routine testing of other targets when the CAP/IASLC/AMP guidelines were finalized, the recommendation was to prioritize EGFR and ALK testing over other molecular markers in order to reserve tissue for these analyses.[6] The type and number of molecular alterations being evaluated ultimately determine how a limited specimen should be used. Immununohistochemical (IHC) and Fluorescent In Situ Hybridization (FISH) are the standard approaches for the detection of protein expression and chromosomal rearrangements and amplifications. Specific single nucleotide polymorphisms (SNPs) that are recognized mutations influencing response to specific therapies demand nucleic acid based tests utilizing a PCR based approach or, in the extreme, DNA sequencing. Most of these assays are typically developed as singleton tests for one specific SNP. As the number of necessary biomarkers increases, efficiency demands multiplexing these singleton assays or adopting a different technology, e.g. Next Gen Sequencing (NGS).[8-10] However, the timeliness for reporting results vary depending on the platform and the number of genes. It needs to be understood that none of these technologies can detect all of the types of genomic alterations of interest and that all of these methodologies must remain in the armamentarium available for proper specimen evaluation. With this in mind, efficient use of limited tissue demands clear communication between oncologists, surgeons, interventional radiologists and pathologists with regard what is needed for patient care and an understanding of available resources, either in house or through an appropriate reference laboratory. A further complexity is the timeliness in obtaining a result. While good practice suggests establishment of institutional protocols, individual patient needs ultimately dictate how best to proceed, emphasizing the importance of good interdisciplinary communication References: 1. Travis, W.D., et al., International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol, 2011. 6(2): p. 244-85. 2. Hung, J.J., et al., Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification on death and recurrence in completely resected stage I lung adenocarcinoma. Ann Surg, 2013. 258(6): p. 1079-86. 3. Song, Z., et al., Prognostic value of the IASLC/ATS/ERS classification in stage I lung adenocarcinoma patients--based on a hospital study in China. Eur J Surg Oncol, 2013. 39(11): p. 1262-8. 4. Gu, J., et al., Prognostic significance of the IASLC/ATS/ERS classification in Chinese patients-A single institution retrospective study of 292 lung adenocarcinoma. J Surg Oncol, 2013. 107(5): p. 474-80. 5. Travis, W.D., et al., Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med, 2013. 137(5): p. 668-84. 6. Lindeman, N.I., et al., Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol, 2013. 8(7): p. 823-59. 7. Leighl, N.B., et al., Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for molecular pathology guideline. J Clin Oncol, 2014. 32(32): p. 3673-9. 8. Rekhtman, N., et al., Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing. J Thorac Oncol, 2011. 6(3): p. 451-8. 9. Sholl, L.M., et al., Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience. J Thorac Oncol, 2015. 10(5): p. 768-77. 10. Gailey, M.P., et al., Multiplatform comparison of molecular oncology tests performed on cytology specimens and formalin-fixed, paraffin-embedded tissue. Cancer Cytopathol, 2015. 123(1): p. 30-9.

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    HOD 04 - Highlights of the Previous Day: Biology, Pathology, Molecular Testing, Prevention, Tobacco Control, Screening and Early Detection (ID 236)

    • Event: WCLC 2015
    • Type: Highlights of the Day
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      HOD04.01 - Biology, Pathology, Molecular Testing (ID 3415)

      07:00 - 08:00  |  Author(s): P. Cagle

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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