Abstract
Background:
Lung adenocarcinoma histologic subtype is an important indicator of patient outcomes so pre-operative knowledge of subtype may be helpful to guide surgical planning. Our aim was to evaluate the sensitivity and prognostic efficacy of CT guided core needle biopsies to predict histologic subtype and patient outcome after surgery.
Methods:
We retrospectively identified 221 patients with lung adenocarcinoma who underwent CT guided lung biopsy and subsequent surgical resection. Concordance, accuracy, specificity, and sensitivity of histologic subtypes from core biopsies were compared with surgically resected specimens. Tumor characteristics and biopsy procedural factors were analyzed to determine impact upon diagnostic sensitivity. Histologic subtype based on biopsy specimen, clinical, tumor, and treatment variables were also examined in relation to time to progression.
Results:
Overall concordance of biopsy samples with predominant subtype from surgical specimens was 77%. Specificity, sensitivity of detecting a non-aggressive or aggressive subtype were 86%, 93% and 95%, 48%, respectively. Length of core specimen and percent subtype composition in the surgically resected specimen were correlated with improved sensitivity, but to a lesser extent with aggressive subtypes. Presence of an aggressive subtype in biopsy specimens was an independent predictor of progression after surgery (P=0.0075, sHR=2.51, 95% CI: 1.28, 4.94).
Conclusions:
CT-guided core biopsies can predict lung adenocarcinoma progression after surgical resection. Future prospective studies should address the role of core biopsy in pre-operative planning.
Keywords: Cancer, Lung cancer, diagnosis, Histology, Pathology
In 2011, the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) introduced a new classification of lung adenocarcinoma [1]. Invasive lung adenocarcinoma was subdivided into five distinct subtypes: lepidic (LEP), acinar (ACI), papillary (PAP), micropapillary (MIP), and solid (SOL). The prognostic utility of the classification system has been well-established since then. In particular, multiple studies have highlighted MIP and SOL histologic subtypes as independent predictors of higher local recurrence rates, distant metastasis, and poorer overall prognosis, even in completely resected early-stage lung adenocarcinoma [2–8]. This has now been adopted by the 2015 WHO classification with only minor modifications [9].
In patients with even a minor component of micropapillary subtype, recurrence rates were lower if patients underwent lobectomy rather than limited resection, emphasizing the importance of identifying the subtype in the pre-operative or intra-operative setting [10]. Processing of intraoperative frozen section specimens can degrade the morphology of the tissue, rendering subtype classification unreliable [11]. Recently, subtype classification based on core biopsy specimens was used to predict patient outcomes after ablation [12] and stereotactic body radiation therapy [13] with the presence of MIP-SOL components strongly associated with worse outcomes. The prognostic potential of histology subtype classification based on core biopsies prior to surgery remains unknown. This was a retrospective study to evaluate concordance of histologic subtype between biopsy specimens and final surgical specimens and to assess whether presurgical biopsy specimens could be used to predict outcomes after lung adenocarcinoma resection.
Patients and Methods
This was a Health Insurance Portability and Accountability Act compliant retrospective single-institution study that was approved by the institutional review board with waiver of informed consent.
Patient Selection
We identified 488 consecutive tumors (in 481 patients) that underwent percutaneous CT guided lung biopsy and subsequent surgical resection at our institution between January 2014 and December 2015. Tumors were excluded if (a) pathology diagnosis was not primary lung adenocarcinoma (n=179), (b) surgical specimen and/or biopsy specimen did not identify any cancer (n=15), (c) pathology diagnosis was adenocarcinoma in situ (AIS) (n=1), mixed adenocarcinoma (n=9), colloid adenocarcinoma (n=1), invasive mucinous adenocarcinoma (n=15), or stage IV adenocarcinoma (n=4), (d) core biopsy was not performed (n=34), (e) or progression could not be determined due to lack of follow up imaging after surgery (n=8). The final cohort included 222 tumors in 221 patients. One patient had two separate lung cancer primary malignancies that were biopsied and resected. A flowchart is provided in Supplemental figure 1. In all cases, biopsies were obtained from the same site as the subsequent surgical resection.
Tissue Acquisition and Histologic Evaluation
Pre-procedure workup, biopsy, and post-procedure care were performed as per our standard practice. All biopsies were performed by a board-certified, fellowship-trained interventional radiologist. Needle biopsy was performed using CT or CT fluoroscopy guidance under conscious sedation. Biopsies were performed coaxially via a 17- or 19-gauge introducer needle. For core needle biopsies, an 18- or 20-gauge semi-automatic spring-loaded core biopsy needle was used (Temno ACT or Temno Evolution, CareFusion, Vernon Hills, IL. or Bard Mission, Bard Peripheral Vascular, Inc. Tempe, AZ). For fine needle biopsy, a 20 or 22 gauge needle was used (Westcott, BD Medical, Franklin Lakes, NJ). Preliminary adequacy of biopsy specimens was assessed intra-operatively by an attending cytopathologist. Sampling of the nodule was performed at the discretion of the interventional radiologist, targeting the area most clearly visible and deemed safe.
Pathology reports were reviewed from biopsy specimens and the subsequent resections, for histologic diagnoses including the presence of any subtype of adenocarcinoma (LEP, ACI, PAP, MIP, or SOL). “Predominant” subtype was based on surgically resected specimens. A meta-category of micropapillary and/or solid (MIP-SOL) was also included to represent aggressive subtypes, which included specimens with micropapillary, solid, or both subtypes. Non MIP-SOL subtypes, including LEP, ACI, and PAP, were grouped as non-aggressive subtypes. The median time between biopsy and surgery was 29 days (range=8 to 259 days).
Follow-up and Assessment
Pulmonary and distant progression after surgery was determined by reviewing radiological imaging, clinical notes, and pathology reports. Time to progression (TTP) was calculated from the time of resection to documented progression evaluated at follow up cross-sectional imaging, or last follow up without progression.
Covariates
Patient characteristics including age, gender, pathology stage at diagnosis, histologic subtype, tumor size, measured length of submitted core biopsy in pathology laboratory, size of the biopsy specimen, number of biopsy cores, biopsy needle gauge, and type of surgical resection. Tumor size followed a log-normal distribution, therefore the log of size measurements was used for univariate and multivariate analyses.
Statistics
Sensitivity, specificity, and accuracy were calculated using standard definitions. Chi-square test was used to test for trend in proportions. Kaplan-Meier method was used to estimate overall survival. Competing-risks proportional hazards model was used to analyze time to progression with death as a competing risk and to obtain a predicted cumulative incidence function. Univariate analysis was performed using this model, and covariates with P<0.15 were included in the multivariate analysis. Backward selection with a cutoff of P=0.05 was performed to select significant predictors of outcome on multivariate analysis. All statistical analyses were performed using R software.
Results
Patient characteristics are summarized in Table 1. The median age was 69 years and there were 88 males and 133 females. Out of 222 tumors, 181 (81.5%) were stage I, 19 (8.6%) were stage II, 17 (7.7%) were stage 3, and 5 (2.3%) were recurrences. The average tumor size at the time of biopsy was 2.1 cm (0.6–8.8 cm) with 85% of the tumors ≤3cm. The distribution of needle passes was as follows: 26 had a 1-core biopsy, 80 had a 2-core biopsy, 71 had a 3-core biopsy, 40 had at least 4 core samples obtained. The number of biopsy cores was undocumented in 10 cases. There was a relatively equal use of the 18G and 20G biopsy needles (n=111 and n=107, respectively), with 4 undocumented cases.
Table 1:
Patient, treatment, and tumor characteristics
| Patient Characteristics | All patients/tumors (N=221/222) |
|---|---|
| Median age, years (range) | 69 (40–84) |
| Sex | |
| Male | 88 (39.8%) |
| Female | 133 (60.2%) |
| Stage | |
| I | 181 (81.5%) |
| II | 19 (8.6%) |
| III | 17 (7.7%) |
| Recurrence | 5 (2.3%) |
| Tumor size (cm) | |
| ≤1.0 | 27 (12.2%) |
| 1.1–2.0 | 107 (48.2%) |
| 2.1–3.0 | 55 (24.8%) |
| 3.1–4.0 | 20 (9.0%) |
| >4.0 | 13 (5.9%) |
| Biopsy size(cm) | |
| ≤0.5 | 37 (16.7%) |
| 0.6–1.0 | 78 (35.1%) |
| 1.1–1.5 | 90 (40.5%) |
| >1.5 | 16 (7.2%) |
| Unknown | 1 (0.5%) |
| Number of biopsy cores | |
| 1 | 26 (11.5%) |
| 2 | 80 (35.2%) |
| 3 | 71 (31.3%) |
| ≥4 | 40 (17.6%) |
| Unknown | 10 (4.4%) |
| Biopsy needle gauge | |
| 18 | 111 (50.0%) |
| 20 | 107 (48.2%) |
| Unknown | 4 (1.8%) |
| Surgery | |
| Limited resection (LR) | 96 (43.2%) |
| Lobectomy (LO) | 126 (56.8%) |
| Histologic subtype at biopsy, surgery | |
| LEP | 98, 147 |
| ACI | 154, 203 |
| PAP | 36, 114 |
| MIP | 33, 90 |
| SOL | 46, 95 |
| MIP-SOL | 73, 143 |
(Lep=lepidic; ACI=acinar; PAP=papillary; MIP=micropapillary; SOL=solid).
Histologic subtypes identified in the biopsy included LEP (n=98), ACI (n=154), PAP (n=36), MIP (n=33), and SOL (n=46). There were 73 in which the biopsy recorded MIP-SOL features (including 6 with both micropapillary and solid subtypes). Histologic subtypes identified in surgical specimen included LEP (n=147), ACI (n=203), PAP (n=114), MIP (n=90), and SOL (n=95), and 143 MIP-SOL (including 42 with both micropapillary and solid subtypes).
Concordance
Overall biopsy concordance with predominant subtype in surgical specimen was 77% (Table 2). Concordance of LEP and ACI subtypes were higher (91% and 86%, respectively), compared with PAP, MIP, and SOL subtypes (54%, 45%, and 62%, respectively). Table 3 summarizes the overall biopsy sensitivity compared to surgical specimens. Similar to concordance with predominant subtype, overall sensitivity with biopsies that had LEP and ACI features was higher (63% and 73%) than those with PAP, MIP, and SOL features (30%, 30%, and 44%). Specificity was high across all subtypes (LEP=93%, ACI=74%, PAP=98%, MIP=95%, SOL=97%), and the overall accuracy did not differ greatly among subtypes (LEP=73%, ACI=73%, PAP=63%, MIP=69%, SOL=74%). Sensitivity (48%) of detecting any aggressive subtype (MIP-SOL) was lower than sensitivity (93%) of detecting any non-aggressive subtypes (not MIP-SOL), (Table 3). However, specificity and accuracy were similar between the two groups. Specificity of detecting MIP-SOL was 95%.
Table 2:
Concordance of predominant histologic subtype between core biopsy and surgical specimens
| LEP | ACI | PAP | MIP | SOL | Overall | |
|---|---|---|---|---|---|---|
| Concordance (%) | 91 | 86 | 54 | 45 | 62 | 77 |
Table 3:
Sensitivity of biopsy for presence or absence of histologic subtype
| LEP | ACI | PAP | MIP | SOL | Not MIP-SOL | MIP-SOL | |
|---|---|---|---|---|---|---|---|
| Sensitivity (%) | 63 | 73 | 30 | 30 | 44 | 93 | 48 |
| Specificity (%) | 93 | 74 | 98 | 95 | 97 | 86 | 95 |
| PPV (%) | 95 | 97 | 94 | 82 | 91 | 92 | 64 |
| NPV (%) | 56 | 21 | 57 | 67 | 70 | 27 | 50 |
| Accuracy (%) | 73 | 73 | 63 | 69 | 74 | 99 | 94 |
(PPV=positive predictive value; NPV=negative predictive value).
Factors affecting concordance
We evaluated multiple factors that could affect concordance including number of biopsy needle passes, biopsy needle gauge, size of the tumor, size of the biopsy specimen, and subtype percent composition in resected tissue (Table 4). We evaluated the total number of specimens in each category as well as compared non-aggressive subtypes (not MIP-SOL) with aggressive subtypes (MIP-SOL) for each category. Increase in the percent subtype composition in the resected specimen was significantly associated with higher sensitivity (χ2(1) =68.134, P<0.001). Percent subtype composition was also significantly associated with sensitivity when non MIP-SOL and MIP-SOL were analyzed separately (χ2(1) =61.3, P<0.001 and χ2(1) =5.58, P=0.018, respectively). Figure 1a indicates that the overall sensitivity of biopsy specimens reached 80% in resected specimen composed of at least 40% of a specific subtype. Sensitivity did not further increase when the percent composition of the subtype was greater than 40%. We also show that for both MIP-SOL and non MIP-SOL, sensitivity increases with the increase of percent subtype composition in the resected specimen. As shown in Figure 1b, increase in length of the biopsy specimen was also associated with higher sensitivity (χ2(1) =5.49, P=0.019). However, when analyzing MIP-SOL and non MIP-SOL separately, only subtypes that were non MIP-SOL were significantly associated with higher sensitivity (χ2(1) =11.7, P<0.001). Biopsy needle gauge and number of needle passes were also not correlated with sensitivity.
Table 4:
Factors affecting biopsy specimen sensitivity with respect to surgical specimens
| Parameter | p-value | χ2 |
|---|---|---|
| Number of biopsy cores | 0.97 | 1.87E-03 |
| Needle gauge | 0.22 | 1.52 |
| Tumor size | 0.53 | 0.39 |
| Length of biopsy | 0.019 | 5.49 |
| Non MIP-SOL | <0.001 | 11.7 |
| MIP-SOL | 0.22 | 1.49 |
| Percent subtype | ||
| composition | <0.001 | 68.1 |
| Non MIP-SOL | <0.001 | 61.3 |
| MIP-SOL | 0.018 | 5.58 |
Figure 1.
(a) Sensitivity of histologic subtype in biopsy by subtype composition (%) in surgical resection. Number of patients in each subgroup delineated below. MIP-SOL, presence of micropapillary and or solid component in biopsy specimen. (b) Sensitivity of histologic subtype by size of core in biopsy. Number of patients in each subgroup delineated below. MIP-SOL, presence of micropapillary and or solid component in biopsy specimen.
Progression
The Kaplan-Meier curve for overall survival is displayed in Supplemental figure 2. The overall survival rate at 1 year was 96.8% (95% CI: 94.5–99.2), at 2 years was 90.9% (95% CI: 87.1–94.9), at 3 years was 86.4% (95% CI: 81.8–91.4). The median overall survival was not reached.
Table 5 summarizes the univariate analysis of time to progression with death as the competing risk. Out of six parameters, three were associated with shorter time to progression: tumor stage (P<0.001, sHR=1.46, 95%CI: 0.59,2.12), tumor size (P=0.013, sHR=8.28, 95%CI: 1.57,43.7), and histologic subtype at biopsy (P<0.001, sHR=3.43, 95%CI: 1.84,6.39). Figure 2 shows the cumulative incidence function generated from the competing risk univariate analysis for histologic subtype at biopsy. The 1-, 2-, 3-, and 4- year cumulative incidences of progression were 4.2%, 9.3%, 12.3%, and 16.0% for not MIP-SOL compared with 18.2%, 25.4%, 29.7%, and 56.1% for MIP-SOL.
Table 5:
Univariate analyses of time to progression with death as competing risk
| Parameter | p-value | sHR | 95%CI |
|---|---|---|---|
| Age | 0.51 | 0.99 | 0.95, 1.02 |
| Sex | |||
| Male | |||
| Female | 0.72 | 1.12 | 0.59, 2.12 |
| Stage | <0.001 | 1.46 | 1.26, 1.69 |
| Tumor size (log) | 0.013 | 8.28 | 1.57, 43.7 |
| Surgery | |||
| Limited resection (LR) | |||
| Lobectomy (LO) | 0.52 | 0.82 | 0.45, 1.50 |
| Histologic subtype at biopsy | |||
| Non MIP-SOL | |||
| MIP-SOL | <0.001 | 3.43 | 1.84, 6.39 |
Figure 2:
Time to progression after surgical resection of specimens with (MIP_SOL) and without (Non MIP_SOL) micropapillary and/or solid components on the CT guided pre-operative biopsy specimen.
Table 6 summarizes the multivariate analysis of time to progression with death as the competing risk. We included the covariates in the univariate analysis with p<0.15 (stage, tumor size, and histologic subtype at biopsy). Histologic subtype at biopsy remained statistically significant (P=0.0075, sHR=2.51, 95%CI: 1.28, 4.94). Tumor stage and size also remained statistically significant (P<0.001, sHR=1.36, 95%CI: 1.148,1.60 and P=0.063, sHR=3.69, 95%CI: 0.93,14.61, respectively).
Table 6:
Multivariate analysis of time to progression with death as competing risk using backward selection with p<0.15 as cut-off.
| Parameter | p-value | sHR | 95%CI |
|---|---|---|---|
| Stage | <0.001 | 1.36 | 1.15, 1.60 |
| Tumor size (log) | 0.063 | 3.69 | 0.93, 14.6 |
| Histologic subtype at biopsy | 0.0075 | 2.51 | 1.28, 4.94 |
Abbreviations: sHR=subdistribution hazard ratio, CI=confidence interval
Comment
The prognostic significance of histological subtypes in lung adenocarcinoma has been well established, and aggressive histological subtypes (MIP, SOL) have been shown to be associated with worse prognosis than non-aggressive subtypes (LEP, ACI, PAP) [7, 14–16]. Intraoperative histological subtype information from frozen sections can be unreliable. Our results showed that overall concordance with predominant subtype was high (77%). Moreover, the presence of aggressive subtype on pre-operative biopsy was an independent predictor of progression after surgical resection, demonstrating the potential utility of CT-guided biopsy for preoperative surgical planning and prognosis. Taken in conjunction with the high specificity for aggressive subtype (95%), these results suggest a potential role for core biopsy in surgical planning for lobectomy vs sublobar resection.
Two recent studies have investigated the concordance between histology subtype in biopsy and surgical specimen in lung adenocarcinoma. Matsuzawa et al. determined that biopsy samples could be reliably used as a predictive marker for predominant histological subtype if the area of the biopsy specimen was sufficiently large [17]. Subsequently, Huang et al. demonstrated low sensitivity for predicting the overall presence of aggressive subtypes, MIP (7.8%) and SOL (16.5%), indicating that surgeons should not rely solely on preoperative biopsies in determining the surgical course [18]. Our report makes several important distinctions relative to the prior studies. First, we show that in fact the histologic subtype based on pre-operative biopsy alone can predict progression after surgery. Second, unlike the prior studies, our work focuses exclusively on CT-guided needle biopsies. This important distinction likely accounts for some of the improved accuracy in our study. This is in line with the study from Huang et al, in which the CT guided biopsies were more concordant with the surgical subtype than the bronchoscopic ultrasound-guided biopsy samples. Relatedly, in Matsuzawa et al, the average size of the samples was 0.69 mm2, and samples >0.7 mm2 had significantly higher concordance rate. The median length of our biopsy samples was 1.04 cm.
Our results revealed that overall concordance with predominant subtype was higher in in LEP and ACI subtypes (91% and 86%, respectively), compared with predominantly aggressive subtypes, SOL (62%) and MIP (45%). This discrepancy may in part be due to fewer tumors with predominantly aggressive subtypes (e.g. there were only 11 MIP predominant tumors). We looked at the sensitivity of biopsy in predicting the presence or absence of histological subtypes. Similar to the concordance data on predominant subtypes, the sensitivity was considerably higher in non-aggressive subtypes (59%) compared to aggressive subtypes (37%).
Sampling technique is an important factor that likely contributes to the variability of biopsy sensitivity. We explored five factors that could affect sampling: number of needle passes, needle gauge, percentage of subtype composition, size of the surgical specimen, and size of the biopsy specimen. Interestingly, the number of needle passes, the gauge, and the size of the surgical specimen had no effect on the sensitivity of the biopsy sample. Both percent subtype composition and increase in size of the biopsy specimen were associated with higher sensitivity. But interestingly, there were differences between aggressive and non-aggressive subtypes noted in the curves for subtype composition and for size of biopsy specimen. For example, increase in subtype composition was associated with increased sensitivity, but in the MIP-SOL group, sensitivity plateaued after subtype composition reached 40% (Figure 1a). In addition, the association between size of biopsy specimen and higher sensitivity was only evident in the non-aggressive subtypes. Increased length of the biopsy specimen did not yield greater sensitivity for the MIP or SOL subtypes (Figure 1b). These differences in the two groups have to be interpreted with caution as the numbers of MIP-SOL specimens with high histology percent composition or with long core biopsies were lower. However, this observation may explain why the MIP-SOL subtypes have worse overall sensitivity, as greater sampling (with higher histology subtype or longer cores) only improves the non MIP-SOL group. It is possible that the spatial distribution of the aggressive subtypes is different and renders needle sampling more difficult. We did not observe any biases in spatial positioning of the needle within the nodule. It is possible that sampling technique is not the only explanation for the decreased sensitivity observed for aggressive subtypes. One alternative explanation that merits further exploration is that aggressive subtypes may be more susceptible to degradation in the biopsy tissue processing steps compared with the non-aggressive subtypes.
The nodules in our cohort had various CT imaging features including solid, subsolid and mixed nodules. Solid regions on CT are thought to be associated with invasive components of adenocarcinoma, but the relationship between established CT imaging features and histology subtype is unknown. In general, the solid region of mixed nodules was more likely to be targeted if deemed safe and feasible; however, evaluation of the position of the needle within the nodule during the procedure is limited given the small size of the nodules and presence of perilesional hemorrhage.
There are several limitations to this study. First, this was a retrospective study from a single institution. CT guided core needle biopsies are performed at a high volume in our institution, potentially limiting the generalizability of these results. There were possible effects of inter-observer variability, including multiple pathologists reviewing the biopsy and surgical specimens [10, 18]. There is “substantial agreement” between thoracic pathologists regarding histologic patterns using frozen section [11], although the kappa for specific subtypes and “difficult” cases may be significantly lower [19]. Biopsies and surgical specimens at our institution were read by thoracic pathologists. Nevertheless, this is an important inherent bias in our work. Additionally, there were multiple surgeons involved in the resections and multiple interventional radiologists performing the CT guided biopsies. The effect of the latter may have a substantial bias if needle sampling was systematically different among the different interventional radiologists. There were no systematic differences in needle passes, needle gauge, or trajectory that we detected in our cohort. Finally, there were overall fewer predominant aggressive subtypes.
Despite these limitations, our study demonstrates that preoperative biopsies can predict progression after surgery and therefore may play a role in surgical planning. We propose that histological findings on pre-operative biopsies can serve as an important tool for surgeons when deciding whether to pursue a more aggressive approach. Moreover, the variables associated with sensitivity of biopsy suggest a role for studies exploring the spatial distribution of histologic subtypes. Finally, further studies are warranted to understand the decreased sensitivity of aggressive subtypes.
Conclusion
In conclusion, aggressive histological subtype on preoperative biopsy is an independent predictor of shorter time to progression after surgery. Our study supports the utility of histological subtypes as a prognostic indicator in the pre-operative setting and potentially as an aid in pre-operative planning.
Supplementary Material
Supplemental figure 1: Patient selection flow diagram and exclusion criteria
Supplemental figure 2: Kaplan-Meier curve for overall survival
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- 1.Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2011;6(2):244–285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Yoshizawa A, Motoi N, Riely GJ, et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2011;24(5):653–664. [DOI] [PubMed] [Google Scholar]
- 3.Xu L, Tavora F, Burke A. Histologic features associated with metastatic potential in invasive adenocarcinomas of the lung. The American journal of surgical pathology. 2013;37(7):1100–1108. [DOI] [PubMed] [Google Scholar]
- 4.Cha MJ, Lee HY, Lee KS, et al. Micropapillary and solid subtypes of invasive lung adenocarcinoma: clinical predictors of histopathology and outcome. The Journal of thoracic and cardiovascular surgery. 2014;147(3):921–928.e922. [DOI] [PubMed] [Google Scholar]
- 5.Makinen JM, Laitakari K, Johnson S, et al. Nonpredominant lepidic pattern correlates with better outcome in invasive lung adenocarcinoma. Lung cancer (Amsterdam, Netherlands). 2015;90(3):568–574. [DOI] [PubMed] [Google Scholar]
- 6.Tsuta K, Kawago M, Inoue E, et al. The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations. Lung cancer (Amsterdam, Netherlands). 2013;81(3):371–376. [DOI] [PubMed] [Google Scholar]
- 7.Ujiie H, Kadota K, Chaft JE, et al. Solid Predominant Histologic Subtype in Resected Stage I Lung Adenocarcinoma Is an Independent Predictor of Early, Extrathoracic, Multisite Recurrence and of Poor Postrecurrence Survival. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(26):2877–2884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Sica G, Yoshizawa A, Sima CS, et al. A grading system of lung adenocarcinomas based on histologic pattern is predictive of disease recurrence in stage I tumors. The American journal of surgical pathology. 2010;34(8):1155–1162. [DOI] [PubMed] [Google Scholar]
- 9.Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015;10(9):1243–1260. [DOI] [PubMed] [Google Scholar]
- 10.Nitadori J, Bograd AJ, Kadota K, et al. Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm or smaller. Journal of the National Cancer Institute. 2013;105(16):1212–1220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Yeh YC, Nitadori J, Kadota K, et al. Using frozen section to identify histological patterns in stage I lung adenocarcinoma of </= 3 cm: accuracy and interobserver agreement. Histopathology. 2015;66(7):922–938. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Gao S, Stein S, Petre EN, et al. Micropapillary and/or Solid Histologic Subtype Based on Pre-Treatment Biopsy Predicts Local Recurrence After Thermal Ablation of Lung Adenocarcinoma. Cardiovascular and interventional radiology. 2018;41(2):253–259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Leeman JE, Rimner A, Montecalvo J, et al. Histologic Subtype in Core Lung Biopsies of Early-Stage Lung Adenocarcinoma is a Prognostic Factor for Treatment Response and Failure Patterns After Stereotactic Body Radiation Therapy. 2016(1879–355X (Electronic)). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Artinyan A, Nelson R, Soriano P, et al. Treatment response to transcatheter arterial embolization and chemoembolization in primary and metastatic tumors of the liver. HPB : the official journal of the International Hepato Pancreato Biliary Association. 2008;10(6):396–404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Hung JJ, Jeng WJ, Chou TY, 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. Annals of surgery. 2013;258(6):1079–1086. [DOI] [PubMed] [Google Scholar]
- 16.Hung JJ, Yeh YC, Jeng WJ, et al. Predictive value of the international association for the study of lung cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma in tumor recurrence and patient survival. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(22):2357–2364. [DOI] [PubMed] [Google Scholar]
- 17.Matsuzawa R, Kirita K, Kuwata T, et al. Factors influencing the concordance of histological subtype diagnosis from biopsy and resected specimens of lung adenocarcinoma. Lung cancer (Amsterdam, Netherlands). 2016;94:1–6. [DOI] [PubMed] [Google Scholar]
- 18.Huang KY, Ko PZ, Yao CW, et al. Inaccuracy of lung adenocarcinoma subtyping using preoperative biopsy specimens. The Journal of thoracic and cardiovascular surgery. 2017;154(1):332–339.e331. [DOI] [PubMed] [Google Scholar]
- 19.Thunnissen E, Beasley MB, Borczuk AC, et al. Reproducibility of histopathologic subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Modern pathology, 2012; 25(12):1574–1583. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental figure 1: Patient selection flow diagram and exclusion criteria
Supplemental figure 2: Kaplan-Meier curve for overall survival