Connect with us


All rights for the submitted article will be transferred and assigned to Hong Kong Medical Publishing Corporation Limited for the sole right to print, publish, distribute, and sell in all languages and media internationally. The transfer of copyright is deemed effective when the submitted article is accepted for publication. If the submitted article contains any material already protected by prior copyright, the corresponding author will deliver written permission from the present copyright holder to Hong Kong Medical Publishing Corporation Limited for the reproduction of the material in their article.


Real-time intraoperative diagnosis of lung adenocarcinoma high risk histological

Authors: Minim Invasive Surg Oncol

Real-time intraoperative diagnosis of lung adenocarcinoma high risk histological

Yusuke Takahashi
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
Correspondence to:  Yusuke Takahashi, MD, PhD, Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan, Tel: +81-3-3964-1211, Fax: +81-3-5375-6097, E-mail:
Recently, peripheral small-sized adenocarcinoma has been increased as lung cancer screening and radiological examination widely performed. Tumor size is one of the determinants of prognostic outcome in clinically node-negative lung adenocarcinoma (ADC). As one of the minimally invasive surgical options for small-sized adenocarcinoma, sublobar resection has been proposed. Two phase III clinical trials have been ongoing to compare prognostic outcome of sublobar resection with that of lobectomy for early stage non-small cell lung cancer. Despite lack of published evidence of clinical trials, sublobar resection has been increased and more important as population of elderly age increase especially in developed countries. However, high risk histological feature such as micropapillary subtype and tumor spread through air space (STAS) was reportedly associated with significantly higher risk of local recurrence after sublobar resection, but not after lobectomy. Surgical-decision making based on frozen section diagnosis of high risk histological features can be useful to prevent local control failure after minimally invasive sublobar resection. To this end, our aim of this article is to review recently published data in this new topic. There is a little evidence demonstrating diagnostic accuracy of high risk histological features on frozen section to date. Available one published data demonstrated that diagnostic accuracy of STAS is higher than that of micropapillary subtype according to previous literature. Also, presence of STAS was more strongly associated with local recurrence in patients who had undergone sublobar resection. Although further investigations are required for validation of the data, STAS diagnosis on frozen section may shed further light on the path forward for intraoperative surgical decision-making regarding minimally invasive surgery.
Keywords: micropapillary, survival, recurrence, lobectomy, sublobar resection
Cite this article as: Takahashi Y. Real-time intraoperative diagnosis of lung adenocarcinoma high risk histological features: a necessity for minimally invasive sublobar resection. Minim Invasive Surg Oncol, 2017; 1(1):12-19.


Currently, non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths in the world. It has been recognized as one of the major issues in public health. The mortality has been still increasing in both developed and developing countries, despite recent progress in screening and treatment methods [1]. The overall survival rate for all patients diagnosed with NSCLC is approximately 15% [1, 2], which has not changed dramatically despite improved radiological examination as well as introduction of new chemotherapeutic agents. The most common histology is adenocarcinoma (ADC) among NSCLC, which accounts for approximately 50% of cases [2, 3]. In recent years, peripheral small-sized adenocarcinoma has been increased as lung cancer screening and radiological examination widely performed. Approximately 25% of cases are detected at an early-stage [2, 4]. As described in TNM staging system [4], tumor size is one of the determinants of prognostic outcome in early-stage lung ADC, which is currently the primary prognostic factor for disease management. In addition, the incidence in elderly age patients with significant comorbidities has been increasing as population of elderly age increase especially in developed countries [5]. On this background, there must be increased needs of minimally invasive surgery in daily practice. One is minimally invasive approaches including thoracoscopic surgery and robotic surgery, another one is sublobar resection to preserve lung parenchyma. Sublobar resection is considered to preserve postoperative pulmonary function that can cause reduced long-term pulmonary complication such as pneumonia [6].
The new World Health Organization (WHO) classification of lung cancer recommended that lung ADC should be classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive ADC. It also characterized invasive ADC as a heterogeneous mixture of histological subtypes including lepidic (LEP), acinar (ACI), papillary (PAP), solid (SOL), and micropapillary (MIP) subtypes [7]. Particularly, presence of MIP subtype has been shown to be significantly associated with local recurrence only in patients who had undergone sublobar resection [8]. In addition, tumor spread through air space (STAS) that was newly described as a pattern of invasion was reported to strongly correlate to local recurrence after sublobar resection, but not after lobectomy [9]. These data emphasize importance of intraoperative histology-based surgical decision making. However, comparing to studies investigating oncologically appropriate candidate for sublobar resection with preoperatively available factors among early stage NSCLC patients [10-12], there are less numbers of published data to attempt intraoperative diagnosis of the histological subtype or invasion. To this end, we discuss possibility and utility of intraoperative frozen section diagnosis of histological subtype and STAS in this article.
Importance of high risk histological features in surgical decision-making
Lobectomy with systematic lymph node has been the gold standard for treatment of early-stage lung ADC since when Cahan reported it as “radical lobectomy” [13]. Recently, sublobar resection has been increased as a minimally invasive surgical option for early-stage lung ADC tumors ≤ 2 cm [14, 15]. As previous publication demonstrated, predominant subtypes are associated with survival outcomes in patients with early-stage lung ADC [16-18]. Presence of MIP subtypes is an independent risk factor for local recurrence after sublobar resection [8]. Additionally, STAS is also strongly associated with local recurrence after sublobar resection [9]. From these findings, sublobar resection may be insufficient for aggressive tumors. Also, we may be able to extend surgical resection intraoperatively if MIP subtype or STAS present on frozen section of sublobar resection.
The diagnostic accuracy of frozen section -which is bolstered by the clinical benefits of sublobar resection compared with lobectomy [19] and favorable 5-year DFS of patients diagnosed with AIS and MIA-has made it an ideal method for surgeons when selecting candidates eligible for sublobar resections. A recent study by Liu et al. investigated the accuracy of intraoperative frozen section diagnosis of lung ADC tumors ≤2 cm based on the WHO histological classification system [20]. In this retrospective study Liu et al. evaluated 803 patients from Fudan University Shanghai Cancer Hospital database who were diagnosed with clinical stage I peripheral lung ADC ≤3 cm. The patient population was divided into 2 main arms for this study. One arm included 432 patients who had undergone sublobar resection while the other arm included 371 patients who had undergone sublobar resection plus subsequent complementary lobectomy, which was determined based on FS results. Patients diagnosed with adenomatous hyperplasia (AAH) / AIS / MIA had undergone sublobar resection whereas patients diagnosed with invasive ADC had undergone sublobar resection followed by lobectomy. The aim of the study was to evaluate the accuracy of frozen section compared with permanent section in identifying histological subtypes and its usefulness in determining extent of additional surgical intervention. Total concordance rate between frozen section and permanent section diagnosis was 84.4%. Additionally, concordance rate can was 95.9% when AAH, AIS, and MIA were classified together as a low-risk group. Of the 803 patients with stage I peripheral lung ADC ≤3 cm in this study, there were 431 (53.7%) ground glass opacity (GGO) cases with a diagnosis of AAH, AIS, or MIA, which was significantly higher than other cohorts from different regions of the world.
Can frozen section predict histological subtypes of lung ADC accurately?
The validity of this study is strengthened by the large number of patients and effective study design; however, data from only a single institution may be a study limitation. While there is a high concordance rate between frozen section and permanent section in the published literature, no concordance rate for histological subtypes of invasive ADC is available; this should be addressed prior to generalizing this conclusion. It was shown that there is the possibility of errors with frozen section diagnosis due to sampling or interpretation since lung ADC usually consists of various histologic subtypes [7]. Therefore, it is generally difficult to predict histological subtype using frozen section diagnosis. In a report of Yeh et al. [21], frozen section diagnosis for micropapillary and solid subtypes had high specificity (94% and 96%, respectively) but low sensitivity (37% and 69%, respectively). They also performed additional analyses and found sampling errors were the major cause of discrepancy between frozen section and permanent section. The most common frozen section errors were overdiagnosing of MIA as invasive ADC. The degree of invasion is often overestimated using frozen section and it is also very difficult to distinguish MIA from LEP predominant invasive ADC using frozen section. On frozen section slides, alveolar spaces are frequently collapsed, which can cause difficulty to evaluate invasion.
STAS is defined as spread of lung cancer tumor cells into air spaces in the lung parenchyma adjacent to primary tumor [7]. Some studies showed presence of STAS more strongly correlate to higher risk of local recurrence [8, 22, 23]. Remarkably, Kameda et al. reported that the diagnostic sensitivity and specificity of STAS on frozen section were 71 % and 92 %, respectively [24]. These are much higher than those of high grade subtype. STAS thus can be more important histological feature of intraoperative frozen section diagnosis, though further investigations should be required to valid these data.
Bittar et al. [25] investigated histological subtyping of lung ADC according to the IASLC/ERS/ATS classification and suggested that the concordance rate was unsatisfactory mainly because of sampling errors and poor frozen section quality. They also demonstrated relatively small interobserver discrepancy, thereby suggesting that the main cause of discrepancy between frozen section and permanent section is sampling error. In contrast, Motoi et al. [26] reported 98.6% accuracy in histological subtyping using intraoperative frozen section. On the other hand, Liu et al. [20] exclusively investigated small-sized lung nodules that included a considerable number of benign lung nodules and metastatic lung tumors. Herein, we should be aware that diagnostic accuracy can vary depending on proportion of small-sized tumor, technical issues, and level of institution. In the same context, we should reconsider whether FS is representative of whole tumor since lung ADC has remarkable histological heterogeneity. For example, LEP component is often observable on the periphery of invasive ADC. This may contribute to risk of sampling errors. This is why many pathologists often give a diagnosis of “consistent with adenocarcinoma” to withhold deciding whether the tumor is invasive ADC. The other factor affecting accurate diagnosis of lung ADC histologic subtypes is training level of pathologists. It is important that all patient samples analyzed in these types of studies are also reviewed by well-trained thoracic pathologist before adding these samples to the institutional data set. It was proposed that pathologists be trained to sample at least the largest side of the tumor, when possible, to make a frozen section to represent the whole tumor.
An unresolved clinical necessity
As described above, sampling error is largely affected by tumor heterogeneity, which depends on tumor size and subtyping. For example, invasive ADC consisting mostly of LEP subtype is often misdiagnosed as minimally invasive or in situ ADC on frozen section. Although STAS may be more reliably diagnosed on frozen section, sampling error and technical issues including appropriate selection of grossly normal lung parenchyma surrounding tumor and methodology of lung inflation. Despite these issues, investigations of diagnostic accuracy of STAS on frozen section should shed light on clinical application of surgical decision-making based on frozen section diagnosis. If technical details are sophisticated, this approach may result in a lower sampling error rate and can be helpful to determine intraoperatively surgical strategies in the near future.
Although sublobar resection remains a controversial treatment option for stage I lung ADC [27-41], diagnostic accuracy on frozen section in differentiating aggressive tumors that are associated with higher risk of local recurrence among small-sized NSCLC can be improved. Further investigations are required for validation as well as clarification of possible causes for diagnostic discrepancies which may be helpful in generalizing results. Particularly, multi-institutional prospective trials can help valid the accuracy of intraoperative high risk histological features of lung ADC on frozen section. These kinds of studies will also support growing knowledgebase on critical role of real-time diagnosis on FS of lung ADC. Since diagnostic accuracy on frozen section in identifying lung ADC high risk features especially STAS will improve, on-going randomized trials investigating the survival outcome of sublobar resection compared with lobectomy may shed further light on the path forward for intraoperative surgical decision-making based on frozen section.
We thank to Dr. Boris Hristov, Department of General Surgery, Florida International University College of Med, Miami, FL, for his editing assistance.
Conflict of interest
The authors have no potential conflicts of interest to disclose.
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61:69-90.
2. Asamura H, Goya T, Koshiishi Y, Sohara Y, Eguchi K, Mori M, Nakanishi Y, Tsuchiya R, Shimokata K, Inoue H, Nukiwa T, Miyaoka E; Japanese Joint Committee of Lung Cancer Registry. Japanese Lung Cancer Registry study: prognosis of 13,010 resected lung cancers. J Thorac Oncol 2008; 3:46-52.
3. Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG, Shepherd FA.  Non-small-cell lung cancer. Lancet 2011:378:1727-1740.
4. Chen VW, Ruiz BA, Hsieh MC, Wu XC, Ries LA, Lewis DR. Analysis of stage and clinical/prognostic factors for lung cancer from SEER registries: AJCC staging and collaborative stage data collection system. Cancer 2014; 120 Suppl 23:3781-3792.
5. Keenan RJ, Landreneau RJ, Maley RH Jr, Singh D, Macherey R, Bartley S, Santucci T. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg 2004; 78:228-233.
6. Kent MS, Mandrekar SJ, Landreneau R, Nichols F, DiPetrillo TA, Meyers B, Heron DE, Jones DR, Tan AD, Starnes S, Putnam JB Jr, Fernando HC. Impact of Sublobar Resection on Pulmonary Function: Long-Term Results from American Colle of Surgeons Oncology Group Z4032 (Alliance). Ann Thorac Surg 2016; 102:230-238.
7. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I; WHO Panel.. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015; 10:1243-1260.
8. Nitadori J, Bograd AJ, Kadota K, Sima CS, Rizk NP, Morales EA, Rusch VW, Travis WD, Adusumilli PS. Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm or smaller. J Natl Cancer Inst 2013; 105:1212-1220.
9. Kadota K, Nitadori J, Sima CS, Ujiie H, Rizk NP, Jones DR, Adusumilli PS, Travis WD. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015; 10:806-814.
10. Takahashi Y, Horio H, Sakaguchi K, Hiramatsu K, Kawakita M. Significant correlation between urinary N(1), N(12)-diacetylspermine and tumor invasiveness in patients with clinical stage IA non-small cell lung cancer. BMC Cancer 2015; 15:65.
11. Takahashi Y, Horio H, Hato T, Harada M, Matsutani N, Morita S, Kawamura M. Prognostic Significance of Preoperative Neutrophil-Lymphocyte Ratios in Patients with Stage I Non-small Cell Lung Cancer After Complete Resection. Ann Surg Oncol 2015; 22 Suppl 3:S1324-S1331.
12. Shiono S, Abiko M, Sato T. Limited resection for clinical Stage IA non-small-cell lung cancers based on a standardized-uptake value index. Eur J Cardiothorac Surg. 201; 43:e7-e12.
13. Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg 1960; 39:555-572.
14. Keenan RJ, Landreneau RJ, Maley RH Jr, Singh D, Macherey R, Bartley S, Santucci T. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg 2004; 78:228-233.
15. Suzuki K, Koike T, Asakawa T, Kusumoto M, Asamura H, Nagai K, Tada H, Mitsudomi T, Tsuboi M, Shibata T, Fukuda H, Kato H; Japan Lung Cancer Surgical Study Group (JCOG LCSSG). A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011; 6:751-756.
16. Takahashi Y, Ishii G, Aokage K, Hishida T, Yoshida J, Nagai K. Distinctive histopathological features of lepidic growth predominant node-negative adenocarcinomas 3-5 cm in size. Lung Cancer 2013; 79:118-124.
17. Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW, Travis WD. 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. Mod Pathol 2011; 24:653-664.
18. Hung JJ, Jeng WJ, Chou TY, Hsu WH, Wu KJ, Huang BS, Wu YC. Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification on death and recurrence in completely resected stage I lung adenocarcinoma. Ann Surg 2013; 258:1079-1086.
19. Warth A, Muley T, Kossakowski CA, Goeppert B, Schirmacher P, Dienemann H, Weichert W. Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma. Am J Surg Pathol 2015; 39:793-801.
20.  Liu S, Wang R, Zhang Y, Li Y, Cheng C, Pan Y, Xiang J, Zhang Y, Chen H, Sun Y. Precise Diagnosis of Intraoperative Frozen Section Is an Effective Method Guide Resection Strategy for Peripheral Small-Sized Lung Adenocarcinoma. J Clin Oncol 2016; 34:307-313.
21. Yeh YC, Nitadori J, Kadota K, Yoshizaw, Rekhtman N, Moreira AL, Sima CS, Rusch VW, Adusumilli PS, Travis WD. Using frozen section to identify histological patterns in stage I lung adenocarcinoma of ≤ 3 cm: accuracy and interobserver agreement. Histopathology 2015; 66:922-938.
22. Lu S, Eguchi T, Tan KS, Bains S, Kadota K, Rekhtman N, Adusumilli PS, Travis WD. Tumor spread through air space (STAS) in lung squamous cell cancer is an independent risk factor: A competing risk analysis. J Thorac Oncol 2015; 12:S210
23. Masai K, Sukeda A, Yoshida A, Asakura K, Nakagawa K, Sakurai H, Watanabe S, Asamura H, Motoi N. Prognostic impact of tumor spread through air space in limited resection for pstage I lung cancer. J Thorac Oncol 2015; 12:S588.
24. Kameda K, Lu S, Eguchi T, Rekhtman N, Chang J, MontecalvoJ, Nones D, Travis WD, Adusumilli PS. Can tumor spread through air space in lung adenocarcinoma be predicted pre-and intraoperatively? J Thorac Oncol 2015; 12:S209
25. Trejo Bittar HE, Incharoen P, Althouse AD, Dacic S. Accuracy of the IASLC/ATS/ERS histological subtyping of stage I lung adenocarcinoma on intraoperative frozen sections. Mod Pathol 2015; 28:1058-63.
26. Motoi N, Hamanaka W, Oba T, Karita S, Ono H, Saito Y, Sato S, Inamura K, Mun M, Sakao  Y, Okumura S, Ishikawa Y. Evaluation of histologic accuracy pn diagnosis and inasion of small-sized lung cancer using intra-operative frozen section. J Thorac Oncol 2011; 6:S566.
27.  Iwata H. Therapeutic strategy for small-sized lung cancer. Gen Thorac Cardiovasc Surg 2016; 64:450-456.
28.  Sesti J, Donington JS. Sublobar Resection: Ongoing Controversy for Treatment for Stage I Non-Small Cell Lung Cancer. Thorac Surg Clin 2016; 26:251-259.
29.  Beasley MB, Dembitzer FR, Flores RM. Surgical pathology of early stage non-small cell lung carcinoma. Ann Transl Med 2016; 4:238.
30.  Fang W, Xiang Y, Zhong C, Chen Q. The IASLC/ATS/ERS classification of lung adenocarcinoma-a surgical point of view. J Thorac Dis 2014; 6:S552-S560.
31.  Van Schil PE, Sihoe AD, Travis WD. Pathologic classification of adenocarcinoma of lung. J Surg Oncol 2013; 108:320-326.
27.  Lee SM, Goo JM, Park CM, Lee HJ, Im JG. A new classification of adenocarcinoma: what the radiologists need to know. Diagn Interv Radiol 2012; 18:519-526.
32.  Donington JS. Current readings: sublobar resection for non-small-cell lung cancer. Semin Thorac Cardiovasc Surg 2013; 25:22-29.
33.  Cao C, Chandrakumar D, Gupta S, Yan TD, Tian DH. Could less be more?-A systematic review and meta-analysis of sublobar resections versus lobectomy for non-small cell lung cancer according to patient selection. Lung Cancer 2015; 89:121-132.
34.  Cheng AM, Wood DE. Minimally invasive resection of early lung cancers. Oncology (Williston Park) 2015; 29:160-166.
27.  Sihoe AD, Van Schil P. Non-small cell lung cancer: when to offer sublobar resection. Lung Cancer 2014; 86:115-120.
35.  Sakurai H, Asamura H. Sublobar resection for early-stage lung cancer. Transl Lung Cancer Res 2014; 3:164-172.
36.  Okada M. Radical sublobar resection for small-diameter lung cancers. Thorac Surg Clin 2013; 23:301-311.
37.  Blasberg JD, Pass HI, Donington JS. Sublobar resection: a movement from the Lung Cancer Study Group. J Thorac Oncol 2010; 5:1583-1593.
38.  Bilfinger TV, Baram D. Sublobar resection in nonsmall cell lung carcinoma. Curr Opin Pulm Med 2008; 14:292-296.
39.  Okada M. Radical sublobar resection for lung cancer. Gen Thorac Cardiovasc Surg. 2008; 56:151-157.
40. Liao JH, Amin VB, Kadoch MA, Beasley MB, Jacobi AH. Subsolid pulmonary nodules: CT-pathologic correlation using the 2011 IASLC/ATS/ERS classification. Clin Imaging 2015; 39:344-351.
41.  Sardenberg RA, Mello ES, Younes RN. The lung adenocarcinoma guidelines: what to be considered by surgeons. J Thorac Dis 2014; 6:S561-S567.

Popular Articles

Minimally invasive surgery for gallbladder cancer
Full Text | PDF (221 KB)

Review of management options for localized renal cell carcinoma
Full Text | PDF (221 KB)

Evolution and clinical relevance of different staging systems for colorectal can
Full Text | PDF (221 KB)

Advances in laparoscopic surgery for colorectal cancer: fluorescence- guided sur
Full Text | PDF (221 KB)