Abstract
OBJECTIVES
We investigated the role of the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification in predicting occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma.
METHODS
We reviewed lung adenocarcinoma patients who had clinically N2-negative status, were evaluated by preoperative positron emission tomography combined with computed tomography (PET/CT) and had undergone lobectomy or pneumonectomy at Memorial Sloan Kettering Cancer Center (n = 297). Tumours were classified according to the 2011 IASLC/ATS/ERS classification. The associations between occult lymph node metastasis and clinicopathological variables were analysed using Fisher's exact test and logistic regression analysis.
RESULTS
Thirty-two (11%) cN0-1 patients had occult mediastinal lymph node metastasis (pN2) whereas 25% of cN1 patients had pN2 disease. Increased micropapillary pattern was associated with increased risk of pN2 disease (P = 0.001). On univariate analysis, high maximum standard uptake value of the primary tumour on PET/CT (P = 0.019) and the presence of micropapillary (P = 0.014) and solid pattern (P = 0.014) were associated with occult pN2 disease. On multivariable analysis, micropapillary pattern was positively associated with risk of pN2 disease (odds ratio = 3.41; 95% confidence intervals = 1.42–8.19; P = 0.006).
CONCLUSIONS
The presence of micropapillary pattern is an independent predictor of occult mediastinal lymph node metastasis. Our observations have potential therapeutic implications for management of early-stage lung adenocarcinoma.
Keywords: Metastasis, Micropapillary, Lung cancer, Early stage, Non-small cell lung cancer
INTRODUCTION
Lymph node metastasis is perhaps the most important factor in determining the treatment of non-small cell lung cancer (NSCLC). To improve patient survival in small, node-negative NSCLC, it is recommended that they undergo limited resection whereas, for NSCLC patients with hilar lymph node metastasis (N1) and/or mediastinal lymph node metastasis (N2), it is recommended that they undergo anatomical resection with neoadjuvant or adjuvant chemotherapy [1, 2].
Currently, preoperative lymph node staging can be determined using both non-invasive and invasive methods. Non-invasive staging is performed by computed tomography (CT) or 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Positron emission tomography combined with CT (PET/CT) is now regarded as the standard method for non-invasive lymph node staging [3–5]. However, a limitation of FDG-PET/CT staging is its high false-negative rate during identification of lymph node metastasis. A recent meta-analysis, including studies that examined FDG-PET/CT imaging for mediastinal lymph node staging in patients with NSCLC and histological examination of lymph nodes by surgery or biopsy, showed that the pooled sensitivity of PET/CT in identifying mediastinal lymph node metastasis was 68% [6] and the incidence of occult mediastinal lymph node metastases in patients with negative uptake on PET/CT was 7–18% [7]. Invasive methods to establish preoperative lymph node staging included mediastinoscopy, endoscopic ultrasound-guided fine-needle aspiration and endobronchial, ultrasound-guided trans-bronchial needle aspiration. However, the use of invasive methods such as these is not routine, particularly for patients with clinically negative node disease by FDG-PET/CT.
Several previous studies have focused on identifying high-risk populations for occult lymph node metastasis in clinical N2-negative patients [7–9]. These studies reported that risk factors for occult lymph node metastasis included female sex, never smokers, tumours located in the upper or middle lobes [7], centrally located tumours, large tumour size [7, 8], high maximum standard uptake value (SUVmax) of the primary tumour [7, 8], positive N1 nodes on PET [8], adenocarcinoma histology [7] and poorly differentiated tumours.
Histological features are being increasingly recognized as strong predictors of biological behaviour in lung cancers. For example, the predominant histological subtype according to the adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) has been shown to predict clinical outcomes in multiple independent studies [10–12]. Adenocarcinomas with certain histological features, such as micropapillary and solid growth patterns, are more aggressive and have poor prognoses [13, 14]. In contrast, adenocarcinomas with predominant lepidic growth pattern are low-grade tumours with favourable prognoses [11, 12].
In this study, we investigated whether primary tumour histological patterns, in addition to clinical factors, in resected lung adenocarcinomas can predict: (i) occult mediastinal lymph node metastasis (pN2) in clinically N2-negative (cN0-1) tumours and (ii) unexpected lymph node metastasis (pN1-2) in clinically, node-negative (cN0) tumours.
MATERIALS AND METHODS
Patient population
This study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center (MSK). The methods were carried out in accordance with the approved guidelines. In this study, we retrospectively reviewed a consecutive series of patients with ≤5 cm lung adenocarcinoma that were clinically N2 negative by preoperative FDG-PET/CT staging and had undergone surgical resection with curative intent at MSK between January 2007 and May 2009 (n = 422). Disease stage was determined by the seventh edition of the American Joint Committee on Cancer TNM Staging Manual. We excluded patients who had undergone limited resection (wedge resection or segmentectomy; n = 112) and neoadjuvant therapy (n = 4). We also excluded 8 patients with invasive mucinous adenocarcinoma because of limited detection of tumours on PET/CT scans [15] and 1 patient with rare foetal adenocarcinoma. The remaining 297 patients met the inclusion criteria for our study cohort (Fig. 1). All patients received anatomical lobectomy or pneumonectomy with systemic mediastinal lymph node dissection. We considered tumours to be central when their centres were located in the inner one-third of the lung parenchyma on transverse CT imaging [16].
Figure 1:
Study cohort flow chart. Between January 2007 and May 2009, 422 patients with lung adenocarcinoma who were clinically N2-negative by preoperative PET/CT underwent surgical resection in Memorial Sloan Kettering Cancer Center. Patients who had undergone limited resection (wedge resection or segmentectomy; n = 112), patients who received neoadjuvant therapy (n = 4) and patients with invasive mucinous (n = 8) or foetal subtype (n = 1) adenocarcinomas were excluded. The remaining 297 patients met all inclusion criteria for our study cohort. PET: positron emission tomography; CT: computed tomography.
SUVmax on FDG-PET/CT of the primary tumour was collected from patient clinical records. We used 4.0 as a cut-off for SUVmax, which is the same as the threshold used by Kanzaki et al. [7]. This retrospective study was approved by MSK's Institutional Review Board. Clinical data on lung adenocarcinoma cases were collected from our prospectively maintained database.
Histological evaluation
All available haematoxylin and eosin-stained tumour slides of the resected specimens in the study cohort were reviewed by three pathologists (Yi-Chen Yeh, Kyuichi Kadota, and William D. Travis). The percentage of each histological component—lepidic, acinar, papillary, micropapillary and solid pattern—was recorded in 5% increments and tumours were classified according to predominant patterns [10]. If ≥5% of the histological pattern was present in a tumour, it was considered as having the presence of that pattern.
Statistical analysis
All statistical analyses were performed using STATA (Special Edition 9.2; Statacorp, College Station, TX, USA) or SAS v9.2 (SAS Institute, Cary, NC, USA). Fisher's exact test was used to test univariate associations between risk of occult lymph node metastasis and clinicopathological variables. Multivariable analysis was conducted using logistic regression analysis to evaluate independent associations between risk of occult lymph node metastasis and clinicopathological factors. Variables that were significant on univariate analysis were also included in the multivariable analysis. If two variables were significantly correlated, only one of them was included in the multivariate model in order to avoid collinearity problems. Hosmer–Lemeshow test was performed for all models to assess goodness of fit and Nagerkerje pseudo-R2 was calculated. All significance tests were two-sided and used a 5% level of significance.
RESULTS
Patient characteristics
Average patient age was 68 years (range, 32–96 years). Most patients were female (n = 198) and ever smokers (n = 232). Mean tumour size was 2.2 cm (range, 0.3–4.9 cm, standard deviation, 0.96 cm). Based on the IALSC/ERS/ATS classification [10], 8 tumours were minimally invasive adenocarcinomas, 39 were lepidic predominant, 113 were acinar predominant, 53 were papillary predominant, 34 were micropapillary predominant and 50 were solid predominant.
In patients with cN0-1 disease (n = 297), 277 (93%) of them had cN0 disease and 20 (7%) had cN1 disease. There were 226 (76%) patients with pN0 disease, 39 (13%) with pN1 disease and 32 (11%) with pN2 disease. Distribution of patients according to cN (cN0-1) and pN (pN0-2) status is summarized in Fig. 2. Unexpected mediastinal lymph node metastases (pN2) were more frequently identified in patients with cN1 disease (5 of 20 patients with cN1 disease, 25%) than in those with cN0 disease (27 of 277 patients with cN0 disease, 10%) although this difference demonstrated only a borderline statistical significance (P = 0.05). Detailed information on patients with pN2 disease is provided in Supplementary Table S1.
Figure 2:
Distribution of patients according to cN (cN0-1) and pN (pN0-2) status. Of all patients with cN0-1 disease (n = 297), 277 patients had cN0 disease and 20 had cN1 disease. There were 226 (76%) patients with pN0 disease, 39 (13%) with pN1 disease and 32 (11%) with pN2 disease. Unexpected mediastinal lymph node metastases (pN2) were more frequently identified in patients with cN1 disease (25%) in those with cN0 disease (10%). However, this difference only demonstrated a borderline statistical significance (P = 0.05).
Clinicopathological factors associated with occult mediastinal lymph node metastasis in patients with clinically N2-negative disease
The results of univariate analysis for the factors associated with pN2 disease in cN0-1 patients are presented in Table 1. Among the clinical factors, only age and SUVmax were associated with risk of pN2 disease. Patients with pN2 disease were younger than patients with pN0-1 disease (mean age: 63.91 vs 68.23 years old; P = 0.027). The mean SUVmax was higher in patients with pN2 disease than in patients with pN0-1 disease (6.77 vs 4.89; P = 0.019). Other preoperative clinical parameters were not associated with risk of pN2 disease.
Table 1:
Clinicopathological factors associated with occult mediastinal lymph node metastasis in patients with clinically N2-negative disease (n = 297)
| Variables | n | pN0-1 | pN2 | P |
|---|---|---|---|---|
| n (%) | n (%) | |||
| Age (years)a | 68.23 ± 10.13 | 63.91 ± 12.4 | 0.027 | |
| Sex | 0.69 | |||
| Female | 198 | 178 (90) | 20 (10) | |
| Male | 99 | 87 (88) | 12 (12) | |
| Smoking status | 0.65 | |||
| Never | 65 | 57 (88) | 8 (12) | |
| Former and current | 232 | 208 (90) | 24 (10) | |
| pT status | 0.26 | |||
| T1a | 152 | 140 (92) | 12 (8) | |
| T1b | 92 | 79 (86) | 13 (14) | |
| T2a | 53 | 46 (87) | 7 (13) | |
| Tumour location | 0.21 | |||
| Upper and middle | 215 | 195 (91) | 20 (9) | |
| Lower | 82 | 70 (85) | 12 (15) | |
| Tumour location | 0.25 | |||
| Central | 20 | 16 (80) | 4 (20) | |
| Peripheral | 277 | 249 (90) | 28 (10) | |
| SUVmax (primary tumour)a | 4.89 ± 4.31 | 6.77 ± 3.57 | 0.019 | |
| Predominant subtype | <0.001 | |||
| Minimally invasive and lepidic | 47 | 47 (100) | 0 (0) | |
| Acinar | 113 | 97 (86) | 16 (14) | |
| Papillary | 53 | 52 (98) | 1 (2) | |
| Micropapillary | 34 | 26 (76) | 8 (24) | |
| Solid | 50 | 43 (86) | 7 (14) | |
| Lepidic pattern | <0.001 | |||
| Absent | 122 | 99 (81) | 23 (19) | |
| Present | 175 | 166 (95) | 9 (5) | |
| Acinar pattern | 0.23 | |||
| Absent | 16 | 16 (100) | 0 (0) | |
| Present | 281 | 249 (89) | 32 (11) | |
| Papillary pattern | 0.51 | |||
| Absent | 69 | 60 (87) | 9 (13) | |
| Present | 228 | 205 (90) | 23 (10) | |
| Micropapillary pattern | 0.014 | |||
| Absent | 148 | 139 (94) | 9 (6) | |
| Present | 149 | 126 (85) | 23 (15) | |
| Solid pattern | 0.014 | |||
| Absent | 156 | 146 (94) | 10 (6) | |
| Present | 141 | 119 (84) | 22 (16) | |
Significant P-values (<0.05) are shown in bold.
SUVmax: maximum standardized uptake value; SD: standard deviation.
aValues are mean ± SD.
Examination of histological factors revealed that specific predominant subtypes were associated with pN2 disease (P < 0.001) (Table 1). Micropapillary predominant tumours had the highest rate of pN2 disease (24%) compared with the other subtypes (0–14%). Additionally, the absence of lepidic pattern (P < 0.001), the presence of micropapillary pattern (P = 0.014) and the presence of solid pattern (P = 0.014) were significantly associated with an increased risk of pN2 disease. There was an inverse association between the presence of lepidic and solid pattern. When classifying tumours by 0, 5–39, or ≥40% (generally denotes predominant morphology) of micropapillary pattern, as the percentage of micropapillary pattern increased, the risk of pN2 disease also increased (6, 13, and 26%, respectively; P = 0.001) (Fig. 3).
Figure 3:
Distribution of tumours with pN1 and pN2 according to micropapillary pattern percentage in clinically N2-negative tumours. As the percentage of micropapillary pattern increased (0, 5–39, and ≥40%), risk of pN2 disease increased (6, 13 and 26%, respectively; P = 0.001)
Multivariable analysis (Table 2) demonstrated that the presence of micropapillary pattern was positively associated [odds ratios (ORs) = 3.41; 95% confidence intervals (CI) = 1.42–8.19; P = 0.006] and the presence of lepidic pattern was inversely associated with an increased risk of pN2 disease (OR = 0.3; 95% CI = 0.13–0.71; P = 0.006). Age was also inversely associated with an increased risk of pN2 disease (OR = 0.96; 95% CI = 0.93–0.99; P = 0.037). SUVmax on PET/CT was not independently associated with risk of pN2 disease (OR = 1.02; 95% CI = 0.94–1.11; P = 0.59).
Table 2:
Multivariate regression analysis of mediastinal lymph node metastasis (pN2) in cN0-1 patients (n = 297)a
| Variables | Odds ratio | 95% CI | P |
|---|---|---|---|
| Age | 0.96 | 0.93–0.99 | 0.037 |
| Clinical N stage | |||
| cN1 versus cN0 | 2.73 | 0.82–9.00 | 0.1 |
| SUVmax (primary tumour) | 1.02 | 0.94–1.11 | 0.59 |
| Micropapillary pattern | |||
| Present versus absent | 3.41 | 1.42–8.19 | 0.006 |
| Lepidic pattern | |||
| Present versus absent | 0.3 | 0.13–0.71 | 0.006 |
Significant P-values (<0.05) are shown in bold.
CI: confidence interval; SUVmax: maximum standardized uptake value.
aHosmer–Lemeshow goodness-of-fit test did not detect model misspecification (P = 0.1, Pseudo-R2 = 18%).
Because previous studies had shown that patients with cN1 disease were more prone to developing N2 disease [8], we also performed a subgroup analysis on the risk of pN2 disease in patients with cN0 disease only. Results of univariate and multivariate analyses are shown in Supplementary Tables S2 and S3, respectively. The presence of micropapillary pattern was positively associated (OR = 2.75; 95% CI = 1.11–6.85; P = 0.03) and the presence of lepidic pattern was inversely associated with an increased risk of pN2 disease (OR = 0.27; 95% CI = 0.11–0.69; P = 0.006) on multivariate analysis. SUVmax on PET/CT was not independently associated with risk of pN2 disease (OR = 1.02; 95% CI = 0.92–1.13; P = 0.72).
Clinicopathological factors associated with unexpected lymph node metastasis in patients with clinically node-negative disease
Of all patients with cN0 disease (n = 277), 57 (21%) of them had unexpected lymph node metastasis [pN1 (n = 30) and pN2 (n = 27)] on pathological examination (Fig. 2). Results of univariate analysis for the factors associated with unexpected lymph node metastasis (pN1-2 disease) are presented in Table 3. Among clinical factors, only SUVmax was associated with risk of unexpected lymph node disease. The mean SUVmax was higher in patients with pN1-2 disease than in patients with pN0 disease (6.54 vs 4.34; P = 0.001). Centrally located tumours had a higher rate of unexpected node-positive disease compared with peripherally located tumours (41 vs 19%). None of the other clinical parameters were associated with unexpected node-positive disease.
Table 3:
Clinicopathological factors associated with unexpected lymph node metastasis in patients with clinically node-negative disease (n = 277)
| Variables | n | pN0 | pN1-2 | P |
|---|---|---|---|---|
| n (%) | n (%) | |||
| Age (years)a | 68.20 ± 10.03 | 65.96 ± 10.4 | 0.14 | |
| Sex | 0.53 | |||
| Female | 182 | 142 (78) | 40 (22) | |
| Male | 95 | 78 (82) | 17 (18) | |
| Smoking status | 0.36 | |||
| Never | 59 | 44 (75) | 15 (25) | |
| Former and current | 218 | 176 (81) | 42 (19) | |
| pT status | 0.20 | |||
| T1a | 145 | 121 (83) | 24 (17) | |
| T1b | 84 | 64 (76) | 20 (24) | |
| T2a | 48 | 35 (73) | 13 (27) | |
| Tumour location | 0.74 | |||
| Upper and middle | 201 | 161 (80) | 40 (20) | |
| Lower | 76 | 59 (78) | 17 (22) | |
| Tumour location | 0.056 | |||
| Central | 17 | 10 (59) | 7 (41) | |
| Peripheral | 260 | 210 (81) | 50 (19) | |
| SUVmax (primary tumour)a | 4.34 ± 3.64 | 6.54 ± 4.36 | 0.001 | |
| Predominant subtype | <0.001 | |||
| Minimally invasive and lepidic | 47 | 46 (98) | 1 (2) | |
| Acinar | 107 | 83 (78) | 24 (22) | |
| Papillary | 49 | 41 (84) | 8 (16) | |
| Micropapillary | 33 | 23 (70) | 10 (30) | |
| Solid | 41 | 27 (66) | 14 (34) | |
| Lepidic pattern | <0.001 | |||
| Absent | 109 | 73 (67) | 36 (33) | |
| Present | 168 | 147 (88) | 21 (13) | |
| Acinar pattern | 0.74 | |||
| Absent | 14 | 12 (86) | 2 (14) | |
| Present | 263 | 208 (79) | 55 (21) | |
| Papillary pattern | 0.59 | |||
| Absent | 61 | 47 (77) | 14 (23) | |
| Present | 216 | 173 (80) | 43 (20) | |
| Micropapillary pattern | <0.001 | |||
| Absent | 136 | 120 (88) | 16 (12) | |
| Present | 141 | 100 (71) | 41 (29) | |
| Solid pattern | <0.001 | |||
| Absent | 153 | 133 (87) | 20 (13) | |
| Present | 124 | 87 (70) | 37 (30) | |
Significant P-values (<0.05) are shown in bold.
SUVmax: maximum standardized uptake value; SD: standard deviation.
aValues are mean ± SD.
Similar to the unexpected pN2 disease analysis, predominant histological subtypes were associated with risk of unexpected node-positive disease (P < 0.001). Solid predominant tumours had the highest rate of unexpected node-positive disease (34%), followed by micropapillary predominant tumours (30%). Additionally, the absence of lepidic pattern (P < 0.001), the presence of micropapillary pattern (P < 0.001) and the presence of solid pattern (P < 0.001) were significantly associated with an increased risk of unexpected node-positive disease.
For our multivariable analysis of predictors for occult lymph node metastasis (pN1-2) in cN0 patients (Table 4), micropapillary pattern was positively associated (OR = 2.82; 95% CI = 1.46–5.45; P = 0.002) and lepidic pattern was inversely associated with risk of unexpected node-positive disease (OR = 0.39; 95% CI = 0.2–0.76; P = 0.006). SUVmax on PET/CT was associated with risk of unexpected node-positive disease at borderline statistical significance (OR = 1.08; 95% CI = 0.99–1.16; P = 0.06).
Table 4:
Multivariate regression analysis of lymph node metastasis (pN1-N2) in cN0 patients (n = 277)a
| Variables | Odds ratio | 95% CI | P |
|---|---|---|---|
| SUVmax (primary tumour) | 1.08 | 0.99–1.16 | 0.06 |
| Micropapillary pattern | |||
| Present versus absent | 2.82 | 1.46–5.45 | 0.002 |
| Lepidic pattern | |||
| Present versus absent | 0.39 | 0.2–0.76 | 0.006 |
Significant P-values (<0.05) are shown in bold.
CI: confidence interval; SUVmax: maximum standardized uptake value.
aHosmer–Lemeshow goodness of fit test did not detect model misspecification (P = 0.14, Pseudo-R2 = 17%).
Because previous studies had demonstrated that PET/CT had lower accuracy in diagnosing lymph node metastasis in patients with a central tumour location, we performed additional subgroup analysis on the risk of unexpected node-positive disease in patients with peripherally located tumours only. Results of univariate and multivariate analyses are given in Supplementary Tables S4 and S5, respectively. The presence of micropapillary pattern was positively associated (OR = 2.78; 95% CI = 1.4–5.52; P = 0.004) and the presence of lepidic pattern was inversely associated with an increased risk of unexpected node-positive disease (OR = 0.4; 95% CI = 0.2–0.82; P = 0.013) on multivariate analysis. SUVmax on PET/CT was also associated with risk of unexpected node-positive disease (OR = 1.08; 95% CI = 1.0–1.17; P = 0.048).
DISCUSSION
We have demonstrated that histological patterns of surgically resected lung adenocarcinoma, particularly identification of the presence of micropapillary pattern and the absence of lepidic pattern, are independent predictors of occult mediastinal lymph node metastasis (pN2) in cN0-1 patients and are also independent predictors of unexpected lymph node metastasis (pN1-2) in cN0 patients. These previously unpublished observations have potential implications for therapeutic management of early-stage lung adenocarcinoma.
In our study cohort, incidence of pN2 disease in cN0-1 patients was 11% and that of pN1-2 disease in cN0 disease was 21%. These results were consistent with data reported by previous studies. We investigated multiple clinical factors that had been previously reported to predict occult lymph node metastasis. Among the factors, only primary tumour SUVmax on PET/CT was significantly associated with a risk of occult lymph node metastasis on univariate analysis; however, this significance was not confirmed on multivariable analysis. These associations may be attributed to differences in the study cohorts—our study focused only on lung adenocarcinoma whereas all of the previous study cohorts included a mixture of different NSCLC histologies. It is well known that lung adenocarcinoma has a strong association with female sex, non-smoking status and peripheral tumour location.
Previous studies by our group [14] and others [13, 17] have shown that micropapillary and solid patterns are indicators of aggressive biological behaviour associated with lymphovascular invasion, pleural invasion, lymph node metastasis, advanced stage and poor prognosis. On the contrary, lepidic pattern has been shown to correlate with a more favourable outcome and is associated with low metastatic potential [18, 19]. The predicative value of the 2011 IASLC/ATS/ERS classification system for lung adenocarcinoma, which was based on classification by predominant patterns (lepidic, acinar, papillary, micropapillary and solid), was initially reported by our group [11]. It has since been validated in large independent cohorts from multiple countries [12]. However, correlations between those histological patterns and occult lymph node metastases remain unknown. In this study, we showed that both the presence of micropapillary pattern and the absence of lepidic pattern were independent risk factors for occult lymph node disease. Furthermore, tumours with predominant (≥40%) micropapillary pattern had a higher rate of occult lymph node disease than those with either 0% or <40% micropapillary pattern. These observations may further emphasize the clinical significance of histological patterns in lung adenocarcinoma.
Information about histological patterns can be obtained, not only in the postoperative surgical specimens, but also in preoperative biopsy specimens and intraoperative frozen sections. As demonstrated in our study, the presence of micropapillary or solid patterns was associated with increased risk of occult lymph node metastasis. Identification of these histological patterns in preoperative biopsy specimens or intraoperative frozen sections may alert the clinician to a higher possibility of occult lymph node metastasis in the patient. We recently reported that while intraoperative frozen section could accurately predict micropapillary and solid histological patterns in surgically resected specimens (>90% for both), the method's sensitivity was relatively unsatisfactory (37 and 69%, respectively) [20]. Determining whether the low sensitivity of frozen section analysis in predicting the final histological pattern could be improved, requires further investigation. For preoperative biopsy specimens, a previous study showed that histological patterns obtained from biopsy specimens were predictive of patient prognosis [21]. However, the correlation between preoperative biopsy and postoperative surgical specimens has yet to be determined. Predictive value of histological patterns in preoperative biopsies, with regard to occult lymph node metastasis, remains to be investigated.
Recently, several reports have shown that radiological parameters, such as ground-glass opacity ratio, tumour disappearance rate and consolidation diameter in thin-section CT, are predictive of prognosis and could be helpful in identifying candidates for sublobar resection [22–24]. Although we were unable to evaluate these parameters in our study, it would be interesting to further investigate whether histological features integrated with radiological parameters could predict occult lymph node metastasis more accurately.
Our study has limitations. Firstly, FDG-PET is less accurate in the evaluation of pulmonary nodules <1 cm and frequently shows false-negative results [25]. This might be a confounding factor in this study. However, in our study cohort of 297 patients, there were only 11 tumours <1 cm (3.7%) and a subgroup analysis that excluded these small tumours did not reveal significantly different results (data not shown). Another limitation of this study is its retrospective, single-institution nature; the possibility of selection bias may not be excluded. A multi-institutional study will help clarify this uncertainty. Finally, while our study did enrol a large population of 297 patients with cN0-1 disease, total number of patients with occult lymph node metastases was still low. This might, in turn, limit the ability to detect factors that may have weak to moderate associations with occult lymph node metastasis.
In conclusion, our study demonstrates that, based on preoperative clinical nodal staging by PET/CT and tumour slide review of surgically resected specimens, the presence of micropapillary pattern and the absence of lepidic pattern are significantly associated with a risk occult mediastinal lymph node disease (pN2) in patients with clinically N2-negative tumours (cN0-1) and unexpected lymph node metastasis (pN1-2) in patients with clinically node-negative tumours (cN0). The correlations between occult lymph node disease and histological patterns evaluated with both preoperative (small biopsy) and intraoperative specimens (frozen section) should be investigated for clinical decision-making in surgical procedures and neoadjuvant therapy.
SUPPLEMENTARY MATERIAL
Funding
The authors' laboratory work is supported by grants from the National Institutes of Health (R21 CA164568-01A1, R21 CA164585-01A1, R01 CA136705-06, U54 CA137788, P30 CA008748 and P50 CA086438-13) and the U.S. Department of Defense (PR101053 and LC110202).
Conflicts of interest: None declared.
Supplementary Material
ACKNOWLEDGEMENTS
We thank Joe Dycoco of the MSK Thoracic Surgery Service for assisting with the MSK Thoracic Surgery Service's Lung Adenocarcinoma Database and Alex Torres of the MSK Thoracic Surgery Service for his editorial assistance.
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