Is there significance in identification of non-predominant micropapillary or solid components in early-stage lung adenocarcinoma?

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1 Interactive CardioVascular and Thoracic Surgery 24 (2017) doi: /icvts/ivw283 Advance Access publication 5 September 2016 Cite this article as: Zhao Z-R, To KF, Mok TSK, Ng CSH. Is there significance in identification of non-predominant micropapillary or solid components in earlystage lung adenocarcinoma? Interact CardioVasc Thorac Surg 2017;24: a b c Is there significance in identification of non-predominant micropapillary or solid components in early-stage lung adenocarcinoma? Ze-Rui Zhao a,kafaito b, Tony S.K. Mok c and Calvin S.H. Ng a, * Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China * Corresponding author. Division of Cardiothoracic Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T. Hong Kong, SAR, China. Tel: ; fax: ; calvinng@surgery.cuhk.edu.hk (C.S.H. Ng). Received 13 February 2016; received in revised form 12 July 2016; accepted 28 July 2016 Abstract A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was in early-stage lung adenocarcinomas, does the presence of non-predominant micropapillary (MIP) or solid (SOL) growth component influence long-term survival and surgical strategy?. Altogether, more than 600 papers were found using the reported search, of which 13 presented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group, study type, relevant outcomes and results of these papers were tabulated. The data collected showed that non-predominant MIP or SOL components in early-stage lung adenocarcinoma can be up to 60.4 and 41.8%, respectively. MIP or SOL components were associated with significantly reduced period of disease-free or overall survival. One study also showed a higher incidence of occult lymph node metastasis in patients with a minor MIP component. Furthermore, the presence of an MIP/SOL component in early-stage adenocarcinomas (ADCs) could influence the oncological outcome following sublobar resection. We conclude that a non-predominant MIP/SOL pattern is a negative prognostic factor and an indicator of early recurrence after limited resection. Keywords: Review Lung adenocarcinoma Micropapillary Solid Surgery Prognosis INTRODUCTION A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1]. THREE-PART QUESTION In [early-stage lung adenocarcinomas], is the presence of [nonpredominant micropapillary or solid growth component] influences the [long-term survival and surgical strategy]? CLINICAL SCENARIO You are working at the thoracic surgery department and are reviewing the histologic reports from patients who have undergone intentional sublobar resection for early-stage lung ADC. You noted that some specimens have demonstrated the presence of a small component of micropapillary or solid growth, while others have not. You are interested about their influence on the surgical outcome and resolve to search the literature yourself. SEARCH STRATEGY The literature research has been performed in Medline from 2003 to 2016 using the PubMed interface. The search strategy was used as follows: (<pulmonary> OR <lung>) AND (<adenocarcinoma>) AND (<micropapillary> OR <solid>) AND (<survival>). SEARCH OUTCOME A total of 677 papers were found and papers were excluded unless the specifically mentioned non-predominant micropapillary or solid growth in early-stage lung adenocarcinomas received curative resection. Of these, 13 papers were identified to offer the best evidence to answer our clinical question and are presented in Table 1. Relevant papers were also identified and their references were screened. RESULTS The 13 studies [2 14] included report the long-term outcomes on 2620 patients with early-stage lung ADCs with non-predominant The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 122 Z.-R. Zhao et al. / Interactive CardioVascular and Thoracic Surgery Table 1: Details of included studies Author, date, journal and country study type (level of evidence Patient group characteristics Outcomes measured Key results Comments Miyoshi et al. (2003), Am J Surg Pathol, Japan [2] 154 Stage I lung ADCs 79.0% (MIP component 5%), 93.0% (MIP < 5%); P = MIP (+): 29.0% Roh et al. (2004), Histopathology, Korea [3] Makimoto et al. (2005), Histopathology, Japan [4] Sanchez-Mora et al. (2008), Hum Pathol, Spain [5] Case series (level IV evidence) Kamiya et al. (2008), Mod Pathol, Japan [6] Nagano et al. (2010), Japan [7] Yeh et al. (2012), J Clin Pathol, Taiwan [8] Sumiyoshi et al. (2013), Japan [9] 35 Stage I lung ADCs 62.5% (MIP component 5%), 52.6% (MIP < 5%); P = Stage I lung ADCs 2 cm 66.0% (MIP component 10%), 93.0% (MIP < 10%); P = Stage I lung ADCs 54.0% (MIP component 5%), 77.0% (MIP < 5%); HR = 3.17, 95% CI: Stage IA lung ADCs 10-year OS 77.6% (MIP component 1%), 98.1% (MIP < 1%); P = % (MIP component 1%), 98.1% (MIP < 1%); P = Stage I lung ADCs 76.0% (MIP component 1%), 96.0% (MIP < 1%); P = Stage I lung ADCs 5-year DFS 53.1% (ADCs with stromal invasion and MIP component 5%), 67.5% (ADCs with stromal invasion but MIP < 5%); P < Stage IA ADCs 5-year DFS 77.6% (MIP component 5%), 92.1% (MIP < 5%); P = % (MIP component 5%), 92.3% (MIP < 5%); P = MIP (+): 45.7% More occult nodal metastasis in MIP (+) cases (62.5 vs 21.1%) MIP (+): 47.1% MIP (+): 41.3% MIP (+): 60.4% MIP (+): 57.1% MIP (+): 35.2% MIP (+): 20.7% Nitadori et al. (2013), J Natl Cancer Inst, USA [10] 734 Stage I ADCs 2cm Lobectomy, n = 476 Limited resection, n = year cumulative incidence of recurrence 19.1, 95% CI: % (MIP component 5%), 12.9, 95% CI: % (MIP < 5%); P = , 95% CI: % (MIP component 5%), 12.4%, 95% CI: % (MIP < 5%); P < MIP (+): 57.5% MIP components associated with increased risk of local recurrence when the surgical margin was less than 1 cm Continued

3 Z.-R. Zhao et al. / Interactive CardioVascular and Thoracic Surgery 123 Table 1: (Continued) Author, date, journal and country study type (level of evidence Patient group characteristics Outcomes measured Key results Comments Zhao et al. (2015), China [11] Jiang et al. (2015), Zhonghua wai ke za zhi [Chin J Surg], China [12] Tsubokawa et al. (2016), Eur J Cardiothorac Surg, Japan [13] Yanagawa et al. (2016), J Thorac Oncol, Japan [14], 201 node-negative ADCs 3cm 5-year DFS MIP or SOL growth who underwent curative resection. All except one study [3] showed that Stage I disease patients with MIP/ SOL-positive ADCs have significantly worse 5-year overall survival and disease-free survival than do those with MIP/SOL-negative tumours (Table 1). Tsubokawa et al. [13] found that the MIP component (greater than or equal to 5% of the tumour quantitatively) negatively influenced the survival of patients with papillary- and acinar-predominant, but not lepidic- or SOL-predominant, tumours. The low percentage of patients with a MIP component may explain why the prognosis of lepidic-predominant ADC is favourable, regardless of MIP. In fact, our previous report [11] also demonstrated that secondary predominant MIP or SOL component was only detected in papillary- and acinar-predominant patients. Moreover, such a secondary predominant MIP or SOL component could help with prognostic stratification of acinar- or papillary-predominant ADCs, which are the most common group of ADCs. Cha et al. [15] suggested that the presence of both MIP and SOL patterns indicated worse survival than that of only one pattern. Although the optimal cut-off value remains controversial, 44.18% (acinar/papillary predominant with secondary predominant MIP or SOL), 64.68% (acinar/papillary predominant without secondary predominant MIP or SOL); HR: 2.19, 95% CI: % (acinar/papillary predominant with secondary predominant MIP or SOL), 85.61% (acinar/papillary predominant without secondary predominant MIP or SOL); HR = 3.03, 95% CI: Stage IB ADCs 5-year DFS Solid component (HR: 1.985, 95% CI: ) and tumour size (HR: 1.941, 95% CI: ) were independent prognostic factors of recurrence for Stage IB ADCs under multivariate analysis 347 clinical Stage IA ADCs Lobectomy, n = 192 Segmentectomy, n =56 Wedge resection, n = Stage I ADCs 5-year DFS 5-year DFS 69.7% (MIP component 5%), 89.3% (MIP < 5%); HR: 1.98, 95% CI: ADC: adenocarcinoma; MIP: micropapillary; SOL: solid; OS: overall survival; DFS: disease-free survival. Underwent wedge resection: 51.4% (MIP component 5%), 93.5% (MIP < 5%); P < Underwent segmentectomy or lobectomy: 76.7% (MIP component 5%), 87.7% (MIP < 5%); P = MIP component 5% versus MIP/SOL negative, HR: 5.49, 95% CI: SOL component 5% versus MIP/SOL negative, HR: 2.73, 95% CI: MIP component 5% versus MIP/SOL negative, HR: 3.39, 95% CI: SOL component 5% versus MIP/SOL negative, HR: 2.45, 95% CI: MIP (+): 9.5% SOL (+): 10.4% SOL (+): 23.8% MIP (+): 14.0%. The study showed that early-stage ADCs with a small component of MIP underwent wedge resection and had worse survival than that of anatomical resection MIP (+): 7% SOL (+): 14% Presence of non-predominant MIP/ SOL leads to comparable survival with MIP/ SOL-predominant tumours the presence of MIP/SOL features is a consistent poor prognostic factor in patients with early-stage lung ADCs. Tissue-sparing resection may be also less than ideal for invasive subtypes containing MIP/SOL components, considering that they carry a significant risk of recurrence. Peripheral lung ADCs less than or equal to 2 cm with an MIP component greater than or equal to 5% showed a higher cumulative incidence of local recurrence after sublobar resection [10]. Furthermore, patients with MIP-positive tumours tended to relapse loco-regionally (63.4%) after limited resection, especially if the surgical margins were less than 1 cm [10]. Of importance, patients who underwent lobectomy showed no difference in the hazard of local recurrence, regardless of the presence of an MIP component. Similarly, Tsubokawa et al. [13] highlighted the importance of anatomical resection in patients with minor MIP components. Recently, the presence of the SOL component in paraffin and frozen sections was also found to correlate with loco-regional recurrence [12, 16]. In addition, having even minor MIP/SOL components are also associated with a higher incidence of occult lymph node

4 124 Z.-R. Zhao et al. / Interactive CardioVascular and Thoracic Surgery metastasis and N1/N2 involvement [3, 17]. Perhaps more importantly, such evidence brings new clinical relevance to the issue of recognizing an MIP or SOL component, preoperatively or intraoperatively, a problem that has received little attention previously. Generally, the presence of a large, solid component within a pulmonary nodule on computed tomography (CT) is more concerning for invasive ADC, but only a few reports have addressed differentiation of the invasive ADC subtypes radiologically. Cha et al.[15] conducted a quantitative analysis to predict the presence of a greater than or equal to 1% MIP or SOL component using radiological parameters. As expected, 72% of the patients with a part-solid nodule were MIP/SOL component-positive, while only one patient with pure ground-glass opacity had such a component. Specifically, a tumour size greater than 2.5 cm, pure solidity and SUVmax greater than or equal to 7 were found to be independent predictors of the presence of an MIP/SOL component for Stage I ADCs. A predictive model combining these three factors showed good accuracy in prediction of the subtype in 49 of 50 ADCs [15]. However, for tumours less than 2.5 cm and those presenting as part-solid nodules on a CT scan, it is still difficult to detect minor MIP/SOL patterns based on current evidence. Intraoperative frozen sections may have more practical significance to identify minor growth components for small pulmonary lesions, as it may guide the magnitude of surgical resection required. By studying the intraoperative capability of identifying a small lesion being diagnosed as preinvasive lesions other than invasive ADCs, Liu et al. [18] found a low disconcordance (4.1% in 803 clinical Stage I ADCs) between frozen and paraffin pathology. However, relatively lower accuracy in predicting the final ADC subtype diagnosis when using frozen sections were reported, ranging from 68 to 69.7% among 473 Stage I cases [16, 19]. Both studies yielded moderate agreement regarding the predominant histological subtype between frozen and permanent sections. Although the incidence of MIP/SOL-predominant cases among early-stage ADCs was low, the presence of such histological patterns was relatively high (46.8% for MIP and 41.8% for SOL among 361 Stage I ADCs [16]; see Table 1). These subtypes with an unfavourable prognosis may influence decision-making on the extent of resection, thus stressing the importance of recognizing the presence or absence of MIP/SOL patterns intraoperatively [10]. In the detection of MIP and SOL patterns using frozen sections to predict histological subtypes, Yeh et al. [16] reported a high specificity (94 and 96%) but low sensitivity (37 and 69%), with satisfactory interobserver agreement. In a similar study, secondary predominant histological patterns were least likely to be identified correctly, with sensitivities ranging from as low as 13.3% for the MIP pattern to 50% for the SOL pattern [19]. However, the specificity was still encouraging, ranging from 95.2% for the SOL pattern to 98.1% for the MIP pattern. Sampling error was able to explain nearly 70% of the discrepancy between frozen versus permanent sections [16]. Smaller tumours were found to be misclassified more often than larger tumours in difficult cases, suggesting that pathologist experience and interpretation error also have a role in the misinterpretation of diagnoses using frozen sections [18, 19]. Additionally, in real-life circumstances, an intraoperative diagnosis needs to be achieved within a limited time span, thus posing great difficulty for pathologists to achieve the same accuracy as with permanent sections, especially when required to detect a minor growth component. Alterations in the expression of cell-matrix adhesion molecules, integrin-associated signalling molecules and apoptosis regulators may lead to anoikis resistance in MIP/SOL cells [6, 7]. Such molecular biology discoveries and proteomic findings in these subtypes can improve our understanding of the complex mechanisms underlying these high-grade histological patterns. Furthermore, such potential biomarkers may one day allow the development of a form of rapid assay to identify MIP/SOL patterns during surgery, thus allowing the optimal extent of resection to be chosen [20]. CLINICAL BOTTOM LINE The presence of non-predominant MIP and SOL patterns in lung ADCs has been associated with poor prognoses and early recurrence, especially after limited resection. The identification of the presence of an MIP/SOL pattern in lung ADCs could help surgeons in choosing the optimal extent of resection and potentially improve patient outcomes. Funding This work was supported by the Chinese University of Hong Kong direct grant [ ]. Conflict of interest: none declared. REFERENCES [1] Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2: [2] Miyoshi T, Satoh Y, Okumura S, Nakagawa K, Shirakusa T, Tsuchiya E et al. Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis. Am J Surg Pathol 2003;27: [3] Roh MS, Lee JI, Choi PJ, Hong YS. Relationship between micropapillary component and micrometastasis in the regional lymph nodes of patients with stage I lung adenocarcinoma. Histopathology 2004;45: [4] Makimoto Y, Nabeshima K, Iwasaki H, Miyoshi T, Enatsu S, Shiraishi T et al. 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