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W.D. Travis



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    E04 - Lung Cancer Pathology Classification (ID 4)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 1
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      E04.4 - Neuroendocrine Tumours (ID 390)

      14:00 - 15:30  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Abstract
      TUMORLETS AND DIFFUSE IDIOPATHIC PULMONARY NE CELL HYPERPLASIA (DIPNECH) Tumorlets are defined as nodular proliferations of NE cells that measure less than 0.5 cm in greatest diameter. Tumorlets typically represent incidental histologic findings found in lung tissues with inflammatory and/or fibrotic lesions such as bronchiectasis, interstitial fibrosis, or infections. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) consists of widespread peripheral airway NE cell hyperplasia and/or multiple tumorlets. These patients are thought to represent a preinvasive lesion for carcinoid tumors because a subset of these patients has one or more carcinoid tumors.[1] DIPNECH may present as multiple pulmonary nodules often mistaken for metastatic cancer or as a form of interstitial lung disease with airway obstruction. Histologically DIPNECH is characterized by prominent NE cell hyperplasia and tumorlets. Some patients also have carcinoid tumors. Tumorlets may cause airway narrowing and/or obliteration. The surrounding lung parenchyma is generally normal.CARCINOID TUMORS Carcinoid tumors most commonly show an organoid growth pattern. The tumor cells show uniform cytologic features with a moderate amount of eosinophilic cytoplasm and finely granular nuclear chromatin. AC are separated from TC by the presence of mitoses between 2 and 10 per 2mm[2] area or the presence of necrosis. Necrosis is usually in the form small punctate foci. Other histologic features such as pleomorphism, vascular invasion and increased cellularity are not as helpful in separating TC from AC. Chromogranin, CD56 and synaptophysin are the most helpful NE immunohistochemical markers. A clear role for Ki-67 in separating TC from AC is not established. However, a low proliferation rate (≤5%) is typically seen in TC compared to AC where it is usually between 5 and 20%. Ki-67 is most useful in addressing the problem of over diagnosis of a high grade tumor in carcinoid tumors where diagnostic criteria are obscured in small crushed biopsies. In this setting a high proliferation rate (>59%) will be found in the high grade LCNEC or SCLC where TC or AC show a much lower proliferation rate.LARGE CELL NEUROENDOCRINE CARCINOMA LCNEC is a high grade NE carcinoma with cytologic features of a non-small cell carcinoma. It was classified as a variant of large cell carcinoma in the 2004 WHO classification.[1] LCNEC are diagnosed according to the following criteria: 1) NE morphology with organoid nesting, palisading or rosette-like structures, 2) high mitotic rate greater than 10 mitoses per 2 mm[2] (average 60-80 mitoses per 2 mm[2]), 3) non-small cell cytologic features including large cell size, low nuclear/cytoplasmic ratio, nucleoli, or vesicular chromatin, and 4) NE differentiation by immunohistochemistry with antibodies such as chromogranin, CD56 or synaptophysin or electron microscopy. The diagnosis of LCNEC is difficult to establish based on small biopsies or cytology. This is because the NE pattern is difficult to see morphologically in small tissue samples or cytology. Also NE differentiation can be difficult to demonstrate by immunohistochemistry in small pieces of tissue. For these reasons the diagnosis of LCNEC requires a surgical lung biopsy. When a LCNEC has components of adenocarcinoma, squamous cell carcinoma, giant cell carcinoma and/or spindle cell carcinoma it is called combined LCNEC. The most common component is adenocarcinoma, but squamous cell, giant cell or spindle cell carcinoma can also occur. If the second component is SCLC the tumor becomes a combined SCLC and LCNEC. NE differentiation must be demonstrated by immunohistochemistry or electron microscopy to diagnose LCNEC. NE immunohistochemical markers are usually best performed as a panel of chromogranin, CD56/NCAM, and synaptophysin. In 41-75% of cases, TTF-1 will be positive. The proliferation index by Ki-67 staining is very with staining of 50-100% of tumor cells .SMALL CELL CARCINOMA The diagnosis of SCLC is established based on small specimens such as bronchoscopic biopsies, fine needle aspirates, core biopsies, and cytology in most all cases, because of the presentation in advanced stages. Fortunately these specimens are diagnostic in most all cases. The diagnosis is based primarily based on light microscopy. Tumor cells appear round to fusiform, growing in sheets and nests. Necrosis is common and is often extensive. Tumor cell cytoplasm is scant and nuclear chromatin is finely granular. Tumor cell size is usually less than the diameter of three small resting lymphocytes. Nucleoli are inconspicuous or absent. A high mitotic rate averages 60-80 per 2 mm[2], however, mitoses can difficult to identify in small biopsy specimens. Combined SCLC is diagnosed when there is also a component of NSCLC such as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, spindle cell carcinoma and giant cell carcinoma. In this setting each of the non-small cell components should be mentioned in the diagnosis. Combined SCLC can be seen in 25% of surgically resected tumors. At least 10% large cells should be present for the diagnosis of combined SCLC/large cell carcinoma; however, for the components of adenocarcinoma, squamous cell or spindle cell carcinoma the amount does not matter. Diagnostic challenges occur in the settings of crush artifact and surgically resected specimens. Crush artifact is common in small biopsy specimens. This can create a problem in separating SCLC from a variety of tumors including non-small cell lung cancer (NSCLC), lymphoma, carcinoid and chronic inflammation. Immunohistochemistry can be very helpful in this setting. In well fixed specimens such as resected specimens the tumor cells of SCLC appear larger than in small biopsies. This often results in over diagnosis of LCNEC. The most important special stain for the diagnosis of SCLC is a good quality H&E stain. However, a panel of immunohistochemical stains is often helpful in the diagnosis. The most common cause of problems in interpretation of biopsies for the diagnosis of SCLC result from sections that are too thick or poorly stained. If the histologic features are classic, it may not be needed. The stains that are useful for the diagnosis of SCLC include a pancytokeratin antibody such as AE1/AE3, CD56, chromogranin and synaptophysin, TTF-1 and Ki-67. If keratin is negative, In 70-80% of SCLC TTF-1 is positive. The main role of Ki-67 is to distinguish SCLC from carcinoids because the proliferation is very high (50-100%) in SCLC.

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    MS16 - ESTS/IASLC Thymic Session (ID 33)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      MS16.1 - Pathological Classification of Thymic Tumours in the Molecular Age: Proposals for the Next WHO Classification (ID 530)

      10:30 - 12:00  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Abstract
      Thymomas are epithelial neoplasms arising in the thymus with a spectrum of morphology, genetic characteristics and clinical behavior. Thymomas are composed of a mixture of neoplastic epithelial cells and non-neoplastic T lymphocytes, admixed in varying proportions. Much of the controversy about classification of thymic epithelial tumors can be attributed to confusion about differences in histologic classification versus grading. While genetic studies have provided some insights into the biology of these tumors and classification, a major hurdle is how to identify molecular abnormalities specific to the epithelial cells of B1 and B2 tumors because the genetic findings are dominated by the numerous lymphocytes in the tumor stroma. Thymic epithelial tumors are classified into thymomas and thymic carcinomas according to the 2004 World Health Organization (WHO). Thymomas are classified into Type A and Type B tumors with the latter being divided into B1, B2 and B3 with an increasing percentage and degree of atypia of epithelial cells and decreasing numbers of lymphocytes. THYMOMA Type A thymoma, is composed of bland spindle or oval shaped and few lymphocytes. Type AB thymoma, , is composed of two components, one resembling the type A thymoma and one with plump cells and predominant lymphocytic infiltrate. Type B1 thymoma, is composed of a prominent lymphocyte population with a minor component of epithelial tumor cells with vesicular nuclei and small nucleoli. Type B2 thymoma, is a thymoma with relatively even mixtures of lymphocytes and plump epithelial cells with vesicular nuclei. Type B3, is predominantly composed of polygonal or round epithelial cells with mild atypia. This category shows variable degree of cytologic atypia. THYMIC CARCINOMA Thymic carcinoma was previously classified as Type C thymoma, but in the 2004 classification this term was dropped. These tumors show much greater degree of cytologic atypia than thymoma. CLASSIFICATION ISSUES Histologic heterogeneity is common, with more than one histologic subtype frequently present in a given tumor, making histologic subclassification difficult. The clinical relevance of the WHO classification system has been validated by many studies. In general the classification from type A to AB, B1, B2 and B3, then thymic carcinoma represent an increasing histologic grade that corresponds to increasing aggressiveness of clinical behavior. Increasing molecular alterations are also found along this spectrum from A to B3 thymoma and thymic carcinoma. Thymic epithelial cells stain for epithelial markers such as keratin and squamous markers such as p63 or p40 while thymic lymphocytes stain for T-cell markers such as TdT and CD3. Type A thymomas tend to have fewer immature (CD1a+) lymphocytes and more mature (CD1a-) lymphocytes, while the type B thymomas have many CD1a+ lymphocytes. PAX8 has been reported to be positive in tumor cells of thymomas. Confusion between histologic classification and grading has led to proposals to collapse the classification into a smaller number of entities. One meta-analysis suggested that the current WHO classification scheme of thymomas could be simplified into three types with significant prognostic value: A/AB/B1, B2, and B3. However, what these authors propose is more of a grading system based on clinical behavior rather than histologic typing. The proposal suggests combining two tumors that are completely different morphologically and genetically (type A and B1) both of which are low grade tumors with indolent clinical behavior. Genetic studies have shown distinct gene expression profiles that support the WHO subclassification of thymomas, as far as the subdivision in type A and B thymomas is concerned. Type AB thymomas are genetically heterogeneous, being more closely related to type B thymomas. Expression of the autoimmune regulator AIRE is lost in approximately 95% of thymomas. Genetic alterations in thymomas are most frequent on chromosome 6p23.3 (major histocompatibility complex locus) and 6q25.2 to 25.3. Thymic carcinoma has a distinctive morphology and biology. It is composed of highly atypical cells with cytoarchitectural features of carcinoma similar to those seen in other organs. Although many lymphocytes can be seen in its stroma, they are of B cell type and mature T cell type. Thymic carcinoma lacks the immature T cell lymphocytes that are present in thymoma. Thymic carcinomas are cytologically malignant.{Travis, 2004 #21463} While a certain amount of necrosis, atypia, and mitoses can be encountered in occasional epithelial thymomas, these findings are common in thymic carcinomas. An infiltrative growth pattern associated with desmoplastic stroma is often seen, without evidence of immature T lymphocytes. Thymic carcinomas display a variety of histologic subtypes, emphasizing the ability of thymic epithelium to differentiate toward different cells: squamous cell carcinoma, basaloid carcinoma, mucoepidermoid carcinoma, lymphoepithelial-like carcinoma, sarcomatoid carcinoma, clear cell carcinoma, adenocarcinoma, and NUT carcinoma with t(15:19) translocation. Several immunohistochemical studies have been employed in an attempt to confirm the diagnosis of thymic carcinoma. Several studies have found that CD5 will stain the epithelial cells of some thymic carcinomas. C-kit (CD117) also frequently stains thymic carcinomas. However, neither of these markers are found in all thymic carcinomas and uncommonly they can be positive in B3 thymomas or carcinomas from other sites such as the lung. Comprehensive genomic analysis using comparative genomic hybridization has shown thymic carcinomas are molecularly distinct from thymomas and squamous cell carcinomas of the lung. While c-Kit expression is common in thymic carcinomas mutations are rare. Despite multiple trials of molecular targeted therapies for the EGFR pathway, angiogenesis inhibition, c-kit pathway, histone deacetylase inhibition, octreotide, an IGF-1 receptor pathway, there are no validated targeted therapies that can be recommended at this time. With some of these approaches in early therapeutic trials, and active molecular investigation of these rare tumors, hopefully, in the near future, new treatment options for patients with advanced disease will become available. So far, molecular studies have provided useful insights into the histologic subtypes of thymic epithelial tumors and provide genetic validation of the existing classification, but they have not demonstrated superiority over morphology in classifying these tumors. Hopefully molecular markers can be identified that will aid in refining the existing classification or in separating the existing subtypes.

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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.05 - Accuracy and Interobserver Agreement in Identifying Histologic Subtypes in Stage I Lung Adenocarcinomas ≤3 cm Using Frozen Section (ID 2590)

      10:30 - 12:00  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      The new IASLC/ATS/ERS classification of lung adenocarcinoma (ADC) histologic subtypes is now recommended for prognostic stratification. The ability to determine histologic subtype accurately by frozen section (FS) may help surgeons to choose limited resection versus anatomic resection in the management of lung ADC. The aim of this study is to investigate the accuracy and interobserver agreement of FS for predicting histologic subtype.

      Methods
      FS and permanent section slides from 361 surgically resected stage I lung ADCs ≤3 cm were reviewed for predominant histologic subtype and presence or absence of lepidic, acinar, papillary, micropapillary, and solid patterns. To determine interobserver agreement, 50 cases were additionally reviewed by 3 pathologists. To test the accuracy of FS in determining degree of invasion in cases with predominantly lepidic growth pattern, 5 pathologists reviewed FS slides from 35 patients and attempted to discriminate between adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant adenocarcinoma (LPA).

      Results

      Parameter Accuracy, % (95% CI) Sensitivity, % (95% CI) Specificity, % (95% CI) κ
      Predominant histologic subtype
      Overall 68 (63–73) Not applicable Not applicable 0.565
      Lepidic 90 (86–92) 75 (64–84) 93 (90–96) 0.681
      Acinar 76 (71-80) 70 (61–77) 79 (73–84) 0.481
      Papillary 85 (81-88) 62 (50–72) 91 (87–94) 0.527
      Micropapillary 94 (91-96) 21 (9–40) 99 (97–100) 0.277
      Solid 91 (88-94) 79 (67–87) 94 (90–96) 0.700
      Presence or absence of each histologic pattern
      Lepidic 80 (76–84) 75 (69–80) 91 (84–96) 0.588
      Acinar 89 (85–92) 90 (86–93) 67 (35–90) 0.252
      Papillary 72 (67–77) 70 (64–75) 79 (69–87) 0.397
      Micropapillary 67 (62–72) 37 (30–45) 94 (89–97) 0.321
      Solid 84 (80–88) 69 (61–76) 96 (92–98) 0.670
      The accuracy of FS for predicting histologic subtype is shown in the Table. There was moderate agreement on the predominant histologic subtype between FS diagnosis and final diagnosis (κ=0.565). FS had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for acinar pattern). All cases of AIS were correctly diagnosed using FS. For MIA, only 41.3% of FS diagnoses were correct, and 52% were overdiagnosed as LPA; for cases of LPA, 79% of FS diagnoses were correct.

      Conclusion
      FS can provide information on the presence of aggressive histologic patterns—micropapillary and solid—with high specificity but low sensitivity. FS is not suitable for determining the predominant pattern or degree of invasion. Although FS can be helpful in diagnosing AIS, it has poor accuracy in distinguishing MIA from LPA.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-007 - Correlating Histologic and Molecular Features in the Lung Adenocarcinoma TCGA Project (ID 1698)

      09:30 - 16:30  |  Author(s): W.D. Travis

      • Abstract

      Background
      Our understanding of the molecular landscape of lung adenocarcinoma (ADC) is evolving rapidly. Furthermore, the IASLC/ATS/ERS lung ADC classification was recently published. The histologic and molecular correlations have not yet been thoroughly explored in this rapidly changing field. We sought to investigate the molecular findings according to the IASLC/ATS/ERS classification. .

      Methods
      Aperio© scanned H&E stained slides were reviewed from 230 tumors according to the 2011 IASLC/ATS/ERS lung adenocarcinoma classification criteria. Molecular profiling was performed on 230 resected, untreated lung adenocarcinomas, using mRNA, miRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. Histologic molecular correlations focused on mRNA and DNA sequencing and TTF-1 proteomic findings.

      Results
      We found 12 lepidic predominant ADC (5%), 21 papillary predominant (9%), 77 acinar predominant (33%), 33 micropapillary predominant (14%), and 58 solid predominant (25%) as well as, 9 invasive mucinous (4%), and 20 unclassifiable ADCs (9%). EGFR mutation and KRAS mutations were found in 8% and 17% of lepidic ADC, respectively. Nine of 12 lepidic ADC (75%) were of the terminal respiratory unit (TRU) gene expression subtype (GES) and 3 (25%)were in the 19p-depleted transcriptional GES, but none were found in the solid-enriched GES (Figure; p=0.007). Most of the papillary ADC were of the TRU (10/21, 47.6%) and 19p-depleted transcriptional (9/21, 42.9%) GES (p=0.026). 46% (41/89) of acinar ADC tumors were in the TRU-GES compared to the solid enriched (18/78, 23.1%) and 19p-depleted transcriptional (18/63, 28.6%) GES (p=0.005). When the oncogene positive group was defined including KRAS, EGFR, ALK, RET, ROS1, BRAF, ERBB2, HRAS and NRAS, there was a higher percentage of solid ADC in the oncogene negative (30/93, 32.3%) compared to the oncogene positive group (28/137, 20.4%, p=0.046). The highest percentage of solid ADC was found in the solid-enriched GES (47/78, 47.4%) compared to the 19p-depleted transcriptional (17/63, 27%) and TRU GES (4/89, 4.5%) (p<0.001). Invasive mucinous ADC correlated with KRAS (but no EGFR) mutations (67%) compared to other ADC (28%, p=0.02) and also lacked elevation of TTF-1 (p=0.007). GES was associated with histologic grade: high grade with solid-enriched GES and intermediate/low grade with TRU GES (p<0.001). Figure 1

      Conclusion
      Our data reveal multiple correlations between molecular (mutation and GES) and histologic (subtyping and grade) features. This reveals insights into the biology of these tumors in particular genetic characteristics of the high grade tumors which may lead to better understanding of why these are more aggressive tumors.