A clinicopathological study of surgically resected lung cancer in patients with usual interstitial pneumonia

Accepted Manuscript A clinicopathological study of surgically resected lung cancer in patients with usual interstitial pneumonia Yasutaka Watanabe, Yoshinori Kawabata, Nobuyuki Koyama, Tomohiko Ikeya, Eishin Hoshi, Noboru Takayanagi, Shinichiro Koyama PII:

S0954-6111(17)30182-8

DOI:

10.1016/j.rmed.2017.06.015

Reference:

YRMED 5191

To appear in:

Respiratory Medicine

Received Date: 28 December 2016 Revised Date:

12 June 2017

Accepted Date: 21 June 2017

Please cite this article as: Watanabe Y, Kawabata Y, Koyama N, Ikeya T, Hoshi E, Takayanagi N, Koyama S, A clinicopathological study of surgically resected lung cancer in patients with usual interstitial pneumonia, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.06.015. 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 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.

ACCEPTED MANUSCRIPT

Title A Clinicopathological Study of Surgically Resected Lung Cancer in Patients with Usual

RI PT

Interstitial Pneumonia All author’s name and affiliations

SC

Yasutaka Watanabe1, 4, 5, Yoshinori Kawabata1, Nobuyuki Koyama4, 5, Tomohiko Ikeya2,

M AN U

Eishin Hoshi2, Noboru Takayanagi3, Shinichiro Koyama4

1

Division of Diagnostic Pathology, and Departments of

2

3

Pulmonary Medicine, Saitama Prefectural Cardiovascular and Respiratory Center, 1696

Thoracic Surgery, and

4

TE D

Itai, Kumagaya City, Saitama, 360-0105, Japan.

Division of Pulmonary Medicine, Clinical Department of Internal Medicine, Jichi

EP

Medical University, Saitama Medical Center, Amanuma-cho, Omiya City, Saitama

5

AC C

330-8503, Japan

Department of Clinical Oncology, Tokyo Medical University Hachioji Medical Center

Address correspondence to: Yasutaka Watanabe, Division of Pulmonary Medicine, Clinical Department of Internal Medicine, Jichi Medical University, Saitama Medical Center, Amanuma-cho, Omiya City, Saitama 330-8503, Japan Tel. +81-48-647-2111; Fax. +81-48-648-5188 E-mail: [email protected]

ACCEPTED MANUSCRIPT

Abstract Background: The clinicopathological characteristics of lung cancer with concomitant

RI PT

usual interstitial pneumonia (UIP) are insufficiently understood. This study aimed to elucidate a characteristic pathological feature of lung cancer that develops in patients

SC

with UIP, with a focus on the location of its onset.

M AN U

Methods: We reviewed surgically obtained specimens, including 547 tumors from 526 patients who underwent lobectomy for lung cancer. Surveyed patients were classified into three groups: patients with UIP (UIP group), patients with lung pathology other than UIP (non-UIP group), and patients without any associated lung pathology (normal

TE D

group). The histology as well as the lobe and location of the onset of lung cancer were compared among these groups. The peripheral location was subdivided into subpleural,

EP

inner and tumor involved centrally secondary to extension.

AC C

Results: The UIP group comprised 82 patients (male, 71 [87%]; mean age, 71 years; smoking rate, 94%), the non-UIP group comprised 334 patients (male, 267 [80%]; mean age, 69 years; smoking rate, 81%), and the normal group comprised 110 patients (male, 33 [30%]; mean age, 63; smoking rate, 29%). No statistical differences were noted in sex, mean age, or smoking index between the UIP and non-UIP groups. Compared with the non-UIP group, the frequency of squamous cell carcinoma (63% vs. 32%), lower

ACCEPTED MANUSCRIPT

lobe origin (76% vs. 32%), and subpleural location (24% vs. 5%) were significantly higher in the UIP group.

region, where UIP is also thought to originate.

RI PT

Conclusions: Lung cancers in patients with UIP show a predilection for the subpleural

SC

Keywords: histology, location, lower lobe, lung cancer, usual interstitial pneumonia

M AN U

(UIP), subpleural location Abbreviations

IPF,Idiopathic pulmonary fibrosis; UIP, usual interstitial pneumonia; ATS, American Thoracic Society; ERS, European Respiratory Society; IIPs, idiopathic interstitial

TE D

pneumonias; NSIP, nonspecific interstitial pneumonia; DIP, desquamative interstitial pneumonia; CLE, centrilobular emphysema; AEF, airspace enlargement with fibrosis;

EP

CPFE, combined pulmonary fibrosis and emphysema; SD, standard deviation; VC,

AC C

volume capacity; WHO, World Health Organization

ACCEPTED MANUSCRIPT

1. Introduction Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease with unknown

RI PT

cause, pathologically presenting with usual interstitial pneumonia (UIP) [1]. IPF/UIP often coexists with lung cancer and emphysema, all of which are more prevalent in

SC

males who are heavy smokers [1–3]. IPF and lung cancer are individually associated

M AN U

with poor clinical outcomes [4,5]. Acute exacerbation of IPF can occur during treatment for cancer and worsens prognosis [6,7]. Lung cancer with concomitant IPF is also highly prevalent in heavy smokers, suggesting the significant impact of smoking on carcinogenesis in these comorbid disorders. However, a previous cohort study reported

TE D

that the presence of IPF but not smoking history is an independent risk factor of lung cancer development [8]. Thus, consensus on the predisposing factor for lung cancer

EP

with concomitant IPF has not been achieved.

AC C

Lung cancer with concomitant IPF mainly consists of squamous cell subtype and is predominantly located at the lower lobe and peripheral location compared with lung cancer without IPF [9–13]. Alveolar epithelial proliferation and/or metamorphosis in the subpleural regions where UIP arises was previously reported to be the possible cause of lung cancer development [14–16]. These findings suggest that lung cancer and IPF may likely develop in the lower lobe and subpleural regions. However, reports on

ACCEPTED MANUSCRIPT

concomitant lung cancer and IPF according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus classification for idiopathic

RI PT

interstitial pneumonias (IIPs) that established standard classification of IIPs including IPF/UIP are not available [17].

SC

Given the hypothesis that lung cancer has a predilection of development in subpleural

M AN U

regions in the lower lobe where UIP arises, we investigated the clinicopathological features of case patients based on the ATS/ERS consensus classification.

2.1.Patients

TE D

2. Materials and Methods

We reviewed the pathological features of 526 patients (male, 371 [71%]; median age,

EP

68 years) who underwent lobectomy or more extensive resection for primary lung

AC C

cancer at the Saitama Prefectural Cardiovascular and Respiratory Center between 2003 and 2007.

2.2. Methods

Clinical records with regard to sex, age, smoking rate, smoking index, resection lobe, and pathology of all patients were available. This retrospective study was approved by

ACCEPTED MANUSCRIPT

the ethical committee at our hospital where this work was performed, and patient consent was not required (April 22, 2008).

RI PT

We examined the resected lungs macro- and microscopically to determine the presence or absence of UIP, nonspecific interstitial pneumonia (NSIP), desquamative interstitial

SC

pneumonia (DIP), centrilobular emphysema (CLE), bulla, airspace enlargement with

M AN U

fibrosis (AEF) [18], and pathological findings in pneumoconioses, such as macroscopic and histological silicotic nodules, mixed dust fibrosis, dust macule, and coal macule. The criteria for UIP, NSIP, and DIP were based on the ATS/ERS consensus classification [17].

The histological classification of lung cancer was based on the

TE D

World Health Organization (WHO) criteria [19]. Patients with carcinoid tumors, adenoid cystic carcinoma, and mucoepidermoid carcinoma were excluded. Diagnosis of

EP

double cancers was based on different histologies or morphologies and/or different

AC C

immunostainings when similar histological features, such as in adenocarcinoma, were present.

A. Classification of patient lungs We classified the resected lungs into three groups as follows (Supplementary Figure 1).

ACCEPTED MANUSCRIPT

1) UIP group: Cases with macroscopically visible and histologically confirmed UIP, including combined pulmonary fibrosis and emphysema (CPFE) [20]. This group also

RI PT

included UIP cases with fibrosis less than 1 cm in depth (histological UIP subgroup), many of which were not clinically diagnosed as IPF (see Table, Fig 1a) [21], and cases

SC

of diffuse UIP with fibrosis more than 1 cm in depth from the pleura (diffuse UIP

M AN U

subgroup).

2) Non-UIP group: Cases with macroscopically or microscopically visible abnormal lung lesions other than UIP as described above.

carcinoma.

TE D

3) Normal group: Cases with normal gross and histologic findings other than

B. Location of lung cancer

EP

We also divided the cases according to the primary location of the tumor as follows: 1) central type: the center of the tumor corresponds to the segmental or larger bronchus

AC C

and 2) peripheral type: the center of the tumor is distal to the subsegmental bronchus. The peripheral type was further subdivided into the following: 1) subpleural: the tumor was widely attached to the visceral pleura (semispheric or zonal in shape, Fig 1b, c); 2) inner lung: the center of the tumor was separate from the pleura with/without some encroachment on the pleura (Fig 1d, e); and 3) tumors that involved the central region secondarily by direct extension from the periphery. 2.3. Statistical analysis

ACCEPTED MANUSCRIPT

Values are presented as percentages or medians with interquartile ranges. Differences and trends among the groups were analyzed using Fisher’s exact test, Mann-Whitney

RI PT

U-test, Kruskal-Wallis test, and the Cochran–Armitage test. A p value <0.05 was considered significant. All subsequent statistical analyses were performed using EZR

SC

software [22]. Total numbers of tumors for histological type, lobe distribution, and

M AN U

location include the double tumors.

3. Results

groups

TE D

3.1. Comparison of clinicopathological features between UIP, non-UIP, and normal

The UIP, non-UIP, and normal groups comprised of 82 (male; 71 [86.6%]; mean age,

EP

71; smoking rate 94%), 334 (male, 267 [80.0%]; mean age; 69, smoking rate 81%), and

AC C

110 patients (male, 33 [30.0%]; mean age, 63; smoking rate, 26%), respectively (Table 1a). The UIP group included two cases each of asbestosis and collagen-related diseases (Supplementary Table 1), and the rest were idiopathic in nature. Meanwhile, the non-UIP group consisted of two NSIP cases, two sarcoidosis, and one pulmonary alveolar proteinosis, but no case of DIP. AEF frequency between the UIP and non-UIP group was statistically different; however, no difference was observed in terms of CLE,

ACCEPTED MANUSCRIPT

bullae, and pathological findings in pneumoconiosis. No difference with respect to sex, age, and smoking index was noted between the UIP and non-UIP groups. However, the

RI PT

normal group showed statistical differences of sex, age, and smoking index compared with the former two groups.

SC

Double primary lung cancers, including 11 tumor nodules within the same lobe, were

M AN U

observed in 21 cases (4 in UIP group, 14 in non-UIP group, and 3 in normal group). Therefore, subsequent analysis for histological type, lobe distribution, and location was conducted in 547 tumors. Histologically, 305 adenocarcinomas, 179 squamous cell carcinomas, 30 large cell carcinomas, 14 pleomorphic carcinomas, 13 adenosquamous

TE D

carcinomas, and 6 small cell carcinomas were noted. The frequency of squamous cell carcinoma and peripheral subpleural location

EP

decreased in the following order: UIP group, non-UIP group, and normal group. The

AC C

frequency of lower lobe distribution was the highest in the UIP group, followed by the normal group, and the lowest in the non-UIP group (Supplementary Figure 2). A total of 83% of cases in the normal group had adenocarcinoma, and none had a subpleural location. A total of 21 cancers in the UIP group and 16 cancers in the non-UIP group had a subpleural location (Table 1b). No double primary lung cancers were noted. Squamous

ACCEPTED MANUSCRIPT

cell carcinomas (66.7% vs. 12.5%) and lower lobe distribution (95.2% vs. 31.2%) were more prevalent in the UIP group than in the non-UIP group. With regard to lesions

RI PT

suspected to have developed into subpleural cancer, the UIP group included 17 cases and 4 with fibrosis other than UIP, whereas the non-UIP group included 11 cases of

SC

various lung lesions in or around the tumor.

M AN U

3.2. Comparison between the histological UIP and diffuse UIP subgroups The incidence of squamous cell carcinomas (71.1% vs. 56.2%) and lower lobe prevalence (89.5% vs. 64.6%) was higher in the diffuse UIP subgroup than in the

4. Discussion

TE D

histological UIP subgroup (Table 2).

EP

To the best of our knowledge, this is the first study to confirm clinicopathological

AC C

differences in three patient groups with lung cancer, namely, lung cancer with UIP, lung cancer with other background pathologies in the lung, and lung cancer without any underlying associated lung pathology according to the ATS/ERS consensus classification. The first two groups showed similarities in sex ratio, age, smoking index, CLE, pathological findings in pneumoconiosis, and bullae ratio. We hypothesized that a comparison of both groups could be performed based on confounding factors.

ACCEPTED MANUSCRIPT

Individuals of the normal group had a low smoking rate and no lung abnormalities; thus, this group served as the normal control. Notably, the preferential localization of lung

RI PT

cancer with UIP to the subpleural region, which has not been previously reported, may shed light on the common pathogenic mechanism of lung cancer and IPF.

SC

Despite the novel finding of subpleural localization in the present study, previous

M AN U

studies have already reported the predominant lower-lobe distribution of lung cancer with UIP [1,9–12]. Lung cancer generally occurs in the upper lobe in smokers, with a high morbidity rate due to emphysema as is the case with the non-UIP group [23]. However, in the present study, lung cancer predominantly occurred in the lower lobe

TE D

even in the UIP group, which had a similar morbidity due to emphysema to the non-UIP group. This result implies that lower lobe resection might increase the possibility of

EP

finding UIP arising from that location. However, lung cancer predominantly emerges

AC C

from the lower lobe in CPFE cases with both UIP in the lower lobe and emphysema in the upper lobe [24]. This finding suggested that UIP might influence lung cancer development more than emphysema. Both UIP and lung cancer are preferentially located at the subpleural region and the lower lobe, whereas all lung cancer lesions in the subpleural region in the UIP group were identified within or around fibrosis including UIP. These data suggest that lung

ACCEPTED MANUSCRIPT

cancer with a significant number of subpleural locations could have originated at the

the fibrosis might occur secondary to lung cancer.

RI PT

area close to the pleura, which is closely related with the occurrence of UIP, although

In the present study, the UIP group, which showed clinicopathological differences

SC

from other groups, further constituted two different subtypes, namely, histological UIP

M AN U

and diffuse UIP. No differences in clinical features by the degree of UIP extent were noted, except for the frequency of lower lobe location between the histological UIP and diffuse UIP subgroups. Histological UIP cases have been previously reported to clinically act like macroscopic cases in terms of acute exacerbations and it is therefore

TE D

possible that these cases may also act clinically similar in terms of lung cancer development [25–27]. Therefore, we consider that including the histological UIP

EP

subgroup in the UIP group is reasonable.

AC C

Furthermore, the UIP group had a higher rate of squamous cell carcinoma than the non-UIP group, including only a comparison between cases with a subpleural location. The factors of male sex and smoking index were not significantly different between the two groups. There are both pathologic and genetic evidence supporting that UIP may be a precursor to development of squamous cell carcinoma. In reports that compared the clinicopathological characteristics between UIP patients with lung cancer and those

ACCEPTED MANUSCRIPT

without lung cancer, many foci of squamous metaplasia and dysplasia were observed at the peripheral area of squamous cell carcinomas [16]. In addition, P53 gene mutation in

RI PT

the UIP lesion might induce squamous cell carcinomas [28,29].

Although the characteristic features of lung cancer with concomitant IPF are detailed,

SC

the present study has some limitations. First, this analysis excluded patients with

M AN U

advanced lung cancer, such as small-cell carcinoma, and advanced IPF and emphysema with low lung function who were ineligible for surgical resection. Therefore, the results of this study may not provide an overview of lung cancer with concomitant IPF. Second, the UIP group included a few cases with interstitial lung diseases other than IPF

molecular

biological

TE D

because of the group classification based on pathological findings. Furthermore, assessments

that

are

a

retrospective

analysis

for

EP

clinicopathological characteristics were not performed. Further approaches for

AC C

molecular biological mechanism underlying lung cancer with concomitant IPF are warranted. Despite these limitations, this study furthers the understanding of the role that UIP may play in lung cancer development.

5. Conclusion

ACCEPTED MANUSCRIPT

Based on the ATS/ERS consensus classification for IIPs, the present study showed that lung cancer occurring as a comorbidity of UIP predominantly develops in the

RI PT

subpleural region of lower lobes where UIP also originates. The findings of this study may shed light on the pathogenic mechanism underlying lung cancer with concomitant

SC

IPF.

M AN U

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author contributions

interpretation.

TE D

YW, YK: Involvement in study concept, study design, writing, data analysis and

EP

IT, EH, TN: Involvement in study concept, data acquisition.

AC C

NK: Involvement in writing, data analysis and interpretation, substantial involvement in revison. SK: Involvement in data analysis and interpretation, substantial involvement in

revision. All authors read and approved the final manuscript. Conflict of interest

ACCEPTED MANUSCRIPT

The authors have no conflict of interest to declare. Acknowledgements

RI PT

We are very grateful for Dr. TV Colby in department of Laboratory Medicine and

AC C

EP

TE D

M AN U

SC

Pathology, Mayo Clinic Arizona, who presented useful suggestions.

ACCEPTED MANUSCRIPT

RI PT

References

[1] G. Raghu, H.R. Collard, J.J. Egan, F.J. Martinez, J. Behr, K.K. Brown, T.V. Colby,

SC

J.F. Cordier, K.R. Flaherty, J.A. Lasky, D.A. Lynch, J.H. Ryu, J.J. Swigris, A.U.

M AN U

Wells, J. Ancochea, D. Bouros, C. Carvalho, U. Costabel, M. Ebina, D.M. Hansell, T. Johkoh, D.S. Kim, T.E. King, Jr., Y. Kondoh, J. Myers, N.L. Muller, A.G. Nicholson, L. Richeldi, M. Selman, R.F. Dudden, B.S. Griss, S.L. Protzko, H.J. Schunemann, An official

ATS/ERS/JRS/ALAT

statement:

idiopathic

pulmonary

fibrosis:

TE D

evidence-based guidelines for diagnosis and management, American journal of respiratory and critical care medicine 183(6) (2011) 788-824.

EP

[2] J.M. Samet, C.L. Wiggins, C.G. Humble, D.R. Pathak, Cigarette smoking and lung

AC C

cancer in New Mexico, The American review of respiratory disease 137(5) (1988) 1110-3.

[3] M. Hardin, M. Foreman, M.T. Dransfield, N. Hansel, M.K. Han, M.H. Cho, S.P. Bhatt, J. Ramsdell, D. Lynch, J.L. Curtis, E.K. Silverman, G. Washko, D. DeMeo, Sex-specific features of emphysema among current and former smokers with COPD, The European respiratory journal 47(1) (2016) 104-112.

ACCEPTED MANUSCRIPT

[4] H. Tsukuma, W. Ajiki, A. Ioka, A. Oshima, Survival of cancer patients diagnosed between 1993 and 1996: a collaborative study of population-based cancer registries in

RI PT

Japan, Japanese journal of clinical oncology 36(9) (2006) 602-607.

[5] M. Natsuizaka, H. Chiba, K. Kuronuma, M. Otsuka, K. Kudo, M. Mori, M. Bando,

SC

Y. Sugiyama, H. Takahashi, Epidemiologic survey of Japanese patients with

M AN U

idiopathic pulmonary fibrosis and investigation of ethnic differences, American journal of respiratory and critical care medicine 190(7) (2014) 773-779. [6] T. Sato, S. Teramukai, H. Kondo, A. Watanabe, M. Ebina, K. Kishi, Y. Fujii, T. Mitsudomi, M. Yoshimura, T. Maniwa, K. Suzuki, K. Kataoka, Y. Sugiyama, T.

TE D

Kondo, H. Date, Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer, The Journal of thoracic and

EP

cardiovascular surgery 147(5) (2014) 1604-1611.e3.

AC C

[7] N. Watanabe, H. Taniguchi, Y. Kondoh, T. Kimura, K. Kataoka, O. Nishiyama, M. Kondo, Y. Hasegawa, Efficacy of chemotherapy for advanced non-small cell lung cancer with idiopathic pulmonary fibrosis, Respiration; international review of thoracic diseases 85(4) (2013) 326-331.

ACCEPTED MANUSCRIPT

[8] R. Hubbard, A. Venn, S. Lewis, J. Britton, Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study, American journal of respiratory and

RI PT

critical care medicine 161(1) (2000) 5-8.

[9] H. Kawasaki, K. Nagai, T. Yokose, J. Yoshida, M. Nishimura, K. Takahashi, K.

SC

Suzuki, R. Kakinuma, Y. Nishiwaki, Clinicopathological characteristics of surgically

M AN U

resected lung cancer associated with idiopathic pulmonary fibrosis, Journal of surgical oncology 76(1) (2001) 53-57.

[10] J. Park, D.S. Kim, T.S. Shim, C.M. Lim, Y. Koh, S.D. Lee, W.S. Kim, W.D. Kim, J.S. Lee, K.S. Song, Lung cancer in patients with idiopathic pulmonary fibrosis, The

TE D

European respiratory journal 17(6) (2001) 1216-1219.[11] T. Lee, J.Y. Park, H.Y. Lee, Y.J. Cho, H.I. Yoon, J.H. Lee, S. Jheon, C.T. Lee, J.S. Park, Lung cancer in

EP

patients with idiopathic pulmonary fibrosis: clinical characteristics and impact on

AC C

survival, Respiratory medicine 108(10) (2014) 1549-1555. [10] K.A. Khan, M.P. Kennedy, E. Moore, L. Crush, S. Prendeville, M.M. Maher, L. Burke, M.T. Henry, Radiological characteristics, histological features and clinical outcomes of lung cancer patients with coexistent idiopathic pulmonary fibrosis, Lung 193(1) (2015) 71-77.[13] H. Matsushita, S. Tanaka, Y. Saiki, M. Hara, K. Nakata, S.

ACCEPTED MANUSCRIPT

Tanimura, J. Banba,

Lung cancer associated with usual interstitial pneumonia,

Pathology international 45(12) (1995) 925-932.

RI PT

[14] E.C. Meyer, A.A. Liebow, RELATIONSHIP OF INTERSTITIAL PNEUMONIA HONEYCOMBING AND ATYPICAL EPITHELIAL PROLIFERATION TO

SC

CANCER OF THE LUNG, Cancer 18 (1965) 322-351.

M AN U

[15] H. Shimizu, [Pathological study of lung cancer associated with idiopathic interstitial pneumonia--with special reference to relationship between the primary site of lung cancer and honeycombing], Nihon Kyobu Shikkan Gakkai zasshi 23(8) (1985) 873-881.

TE D

[16] D.H. Song, I.H. Choi, S.Y. Ha, K.M. Han, J.J. Lee, M.E. Hong, K. Jeon, M.P. Chung, J. Kim, J. Han, Usual interstitial pneumonia with lung cancer:

AC C

10-16.

EP

clinicopathological analysis of 43 cases, Korean journal of pathology 48(1) (2014)

[17]American

Thoracic

Society/European

Respiratory

Society

International

Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and

ACCEPTED MANUSCRIPT

by the ERS Executive Committee, June 2001, American journal of respiratory and critical care medicine 165(2) (2002) 277-304.

RI PT

[18] Y. Kawabata, E. Hoshi, K. Murai, T. Ikeya, N. Takahashi, Y. Saitou, K. Kurashima, M. Ubukata, N. Takayanagi, H. Sugita, S. Kanauchi, T.V. Colby, Smoking-related

SC

changes in the background lung of specimens resected for lung cancer: a

M AN U

semiquantitative study with correlation to postoperative course, Histopathology 53(6) (2008) 707-714.

[19] Tumor of the lung, Eds. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of tumors of the lung, pleura, thymus and heart. Lyon,

TE D

IARCP Press. (2015) 9-151.

EP

[20] V. Cottin, H. Nunes, P.Y. Brillet, P. Delaval, G. Devouassoux, I. Tillie-Leblond, D. Israel-Biet, I. Court-Fortune, D. Valeyre, J.F. Cordier, Combined pulmonary fibrosis

AC C

and emphysema: a distinct underrecognised entity, The European respiratory journal 26(4) (2005) 586-593.

[21] Y. Kawabata, Y. Shimizu, E. Hoshi, K. Murai, T. Kanauchi, K. Kurashima, Y. Sugita, Asbestos exposure increases the incidence of histologically confirmed usual interstitial pneumonia, Histopathology 68(3) (2016) 339-346.

ACCEPTED MANUSCRIPT

[22] Y. Kanda, Investigation of the freely available easy-to-use software 'EZR' for medical statistics, Bone marrow transplantation 48(3) (2013) 452-458.

RI PT

[23] D.M. Skillrud, K.P. Offord, R.D. Miller, Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study, Annals of

SC

internal medicine 105(4) (1986) 503-7.

M AN U

[24] L. Gao, S. Xie, H. Liu, P. Liu, Y. Xiong, J. Da, C. Que, H. Dai, C. Wang, Lung cancer in patients with combined pulmonary fibrosis and emphysema revisited with the 2015 World Health Organization classification of lung tumors, The clinical respiratory journal

(2016) doi: 10.1111/crj.12575.

TE D

[25] Y. Kawabata, K. Fukushima, T. Uchiyama, H. Sugita, B. Kimura, [A focal usual interstitial pneumonia lesion: an important risk factor in diffuse alveolar

EP

damage--acute exacerbation of a focal usual interstitial pneumonia patient], Nihon

AC C

Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 39(5) (2001) 316-321.

[26] J. Araya, Y. Kawabata, P. Jinho, T. Uchiyama, H. Ogata, Y. Sugita, Clinically occult subpleural fibrosis and acute interstitial pneumonia a precursor to idiopathic pulmonary fibrosis?, Respirology (Carlton, Vic.) 13(3) (2008) 408-412.

ACCEPTED MANUSCRIPT

[27] J.G. Parambil, J.L. Myers, J.H. Ryu, Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with connective tissue diseases,

RI PT

Chest 130(2) (2006) 553-558.

[28] H. Kawasaki, T. Ogura, T. Yokose, K. Nagai, Y. Nishiwaki, H. Esumi, p53 gene

SC

alteration in atypical epithelial lesions and carcinoma in patients with idiopathic

M AN U

pulmonary fibrosis, Human pathology 32(10) (2001) 1043-1049.

[29] T. Takahashi, M. Munakata, Y. Ohtsuka, H. Nisihara, Y. Nasuhara, A. Kamachi-Satoh, H. Dosaka-Akita, Y. Homma, Y. Kawakami, Expression and alteration of ras and p53 proteins in patients with lung carcinoma accompanied by

AC C

EP

TE D

idiopathic pulmonary fibrosis, Cancer 95(3) (2002) 624-633.

ACCEPTED MANUSCRIPT

Figure Legends

RI PT

Figure 1 1a. Macroscopic features of usual interstitial pneumonia (within the black line) that is less than 1 cm deep in the lower lobe.

M AN U

usual interstitial pneumonia (UIP) in the lower lobe.

SC

1b. Macroscopic features of a hemispheric shaped mass based on the pleura within

1c. Macroscopic features of a zonal shaped mass based on the pleura that was situated between the UIP and normal lung in the lower lobe.

TE D

1d. Macroscopic features of a spherical or oval shaped mass with pleural indentation (red line) and inner black pigment (surrounding black line) based on the pleura, in UIP with less than 1 cm deep in the lower lobe and normal lung in the lower lobe.

EP

1e. Macroscopic features of an irregular shaped mass in emphysema and adjacent to the

AC C

honeycombing in the upper lobe. 1f. Macroscopic features of a zonal shaped mass based on the pleura within emphysema in the upper lobe.

ACCEPTED MANUSCRIPT

Supplementary Figure 1 The frequency of squamous cell carcinoma (A) and peripheral subpleural location (B)

RI PT

decreased in the following order: UIP group> non-UIP group> normal group. The frequency of lower lobe distribution (C) was highest in the UIP group, followed by the

AC C

EP

TE D

M AN U

SC

normal group, non-UIP group.

ACCEPTED MANUSCRIPT

Table 1a. Comparison of clinicopathological features among the UIP, non-UIP, and normal groups non-UIP group

normal group

p.value

p.value

(UIP group

(UIP group

vs. non-UIP

vs. non-UIP

RI PT

UIP group

group)

group vs. normal group)

Number(*)

82 (86)

334 (348)

110 (113)

male (%)

71 (86.6%)

267 (80.0%)

33 (30.0%)

0.207

<0.001

Age

Mean ± SD

70.5 ± 6.8

68.5± 8.8

63.2 ± 9.7

0.056

<0.001

Smoking rate

81(93.9%)

282 (81.1%)

29(26.3%)

0.004

<0.001

Smoking index

46.8 ± 25.3

40.5 ± 32.8

11.5 ± 24.4

0.108

<0.001

CLE

44 (53.7%)

217 (65.0%)

0 (0%)

0.074

<0.001

Pathological findings

20 (24.4%)

75 (22.5%)

0 (0%)

0.769

<0.001

Bullae

16 (19.5%)

39 (11.7%)

0 (0%)

0.070

<0.001

AEF

14 (17.1%)

19 (5.7%)

0 (0%)

0.002

<0.001

Others**

27 (32.9)

161 (48.2)

0 (0%)

0.013

<0.001

Patient lungs

Adenocarcinoma Squamous cell carcinoma Others

19 (22.1%)

192 (55.2%)

94 (83.2%)

<0.001

54 (62.8%)

111 (31.9%)

14 (12.4%)

<0.001

13 (15.1%)

45 (12.9%)

5 (4.4%)

0.597

AC C

Lobe distribution

<0.001

EP

Histological type

TE D

in pneumoconiosis

M AN U

pack-years

SC

Sex

<0.001

Upper lobe

21 (24.4%)

237 (68.1%)

64 (56.6%)

<0.001

Lower lobe

65 (75.6%)

110 (31.6)

49 (43.4%)

<0.001

Main bronchus

0 (0%)

1 (0.3%)

0 (0%)

Location

1 <0.001

Central type

5 (5.8%)

28 (8.0%)

9 (8.0%)

0.65

Peripheral type a:

21 (24.4%)

16 (4.6%)

0 (0%)

<0.001

Peripheral type b: inner

55 (64.0%)

260 (74.7%)

100 (88.5%)

0.582

Peripheral type c: to central

5 (5.8%)

44 (12.6%)

4 (3.5%)

0.865

subpleural

ACCEPTED MANUSCRIPT

*; the number in parenthesis includes the double tumors and was used for total number

fibrosis were included in non-UIP group.

RI PT

of tumor for histological type, lobe distribution and location **; Regarding the other abnormal findings, 3 bronchioectasis and 24 microscopic respiratory bronchiotitis and/or fibrosis were included in the UIP group and 21 bronchoectasis, 9 old tuberculosis, and 131 microscopic respiratory bronchiotitis and/or

AC C

EP

TE D

M AN U

SC

Abbreviation. UIP; Usual interstitial pneumonia, SD; standard deviation, CLE; centrilobular emphysema, AEF; Airspace enlargement with fibrosis

ACCEPTED MANUSCRIPT

Table 1b. A comparison of the cases with subpleural location between the UIP group and the non-UIP group non-UIP group

21 (21)

16 (16)

19 (90.5%)

12 (75.0%)

0.371

69.8±7.7

73.4 ± 10.0

0.229

19 (90.5%)

12 (75.0%)

0.371

CLE

10 (47.6%)

8 (50.0%)

Pathological findings in pneumoconiosis

3 ( 13.6%)

Bullae

７ (33.3%)

AEF

4 (19.0%)

Sex

male (%)

Age Mean ± SD Smoking rate

SC

Number (*)

0.254

4 (25.0%)

0.723

1 (6.2%)

0.364

13 (61.9%)

2 (12.5%)

0.003

20 (95.2%)

5 (31.2%)

<0.001

Lesions suspected to

TE D UIP

17

other fibrosis 3, AEF 1

AC C

have preceded subpleural cancer

EP

Lower lobe

1

5 (31.2%)

Histological type

Lobe distribution

M AN U

Patient lungs

Squamous cell carcinoma

p.value

RI PT

UIP group

other fibrosis 4, CLE 2 subpleural scar 5 no previous lesion 5

Abbreviation. UIP; Usual interstitial pneumonia, No; Number, SD; standard deviation, CLE; centrilobular emphysema, AEF; Airspace enlargement with fibrosis,

ACCEPTED MANUSCRIPT

Table 2.

Differences between the UIP subgroups histological UIP subgroup***

36 (38)

46 (48)

32 (88.9%)

39 (84.8%)

Age Mean±SD

68.8 ± 6.9

71.9 ± 6.4

0.036

Smoking rate

33 (94.4%)

44 (93.5%)

0.650

Smoking index pack-years

47.1 ± 22.5

47.5 ± 27.3

0.947

86.86 ±16.54

82.61 ± 12.85

0.202

23 (50.0%)

0.508

Sex

male (%)

Pulmonary function %VC ± SD Patient lungs

SC

Number (*)

p.value

RI PT

diffuse UIP subgroup**

0.748

21 (58.3%)

Pathological findings in pneumoconiosis

10 (27.8%)

10 (21.7%)

0.608

Clinical diagnosis of IPF before surgery

36 (100%)

2 (4.3%)

<0.001

5 (13.2%)

14 (29.2%)

0.166

27 (71.1%)

27 (56.2%)

0.183

6 (15.8%)

7 (14.6%)

0.756

4 (10.5%)

17 (35.4%)

0.011

34 (89.5%)

31 (64.6%)

0.011

Central type

2 (5.3%)

3 (6.2%)

Peripheral type a: subpleural

11 (28.9%)

10 (20.8%)

0.453

Peripheral type b:

24 (63.2%)

31 (64.6%)

1

1 (2.6%)

4 (8.3%)

Squamous cell carcinoma Others Lobe distribution

AC C

Upper lobe

TE D

Adenocarcinoma

EP

Histological type

M AN U

CLE

Lower lobe Location

1

inner Peripheral type c: to central

0.378

ACCEPTED MANUSCRIPT

*; the number in parenthesis includes the double tumors and was used for total number of tumor for histological type, lobe distribution and location

RI PT

Diffuse UIP**; UIP subgroup with more than 1 cm in depth from the pleura, Histological UIP***; UIP subgroup with less than 1 cm in depth of fibrosis from the pleura

AC C

EP

TE D

M AN U

SC

Abbreviation.SD; standard deviation, No; Number, VC; volume capacity, UIP; Usual interstitial pneumonia, CLE; centrilobular emphysema, AEF; Airspace enlargement with fibrosis, IPF; interstitial pulmonary fibrosis

ACCEPTED MANUSCRIPT

1b

AC C

EP

TE D

1c

M AN U

SC

RI PT

1a

10mm

ACCEPTED MANUSCRIPT

1e

EP AC C

1f

TE D

M AN U

SC

RI PT

1d

ACCEPTED MANUSCRIPT

Highlights ・ The frequency of histology of lung cancer with concomitant UIP was high in

RI PT

squamous cell carcinoma.

・The frequency of lung cancer with concomitant UIP was high in the lower lobe.

SC

・A quarter of lung cancer cases with concomitant UIP develops in the subpleural

AC C

EP

TE D

M AN U

regions where UIP similarly arises.