Lung Cancerdiagnostic-pathology- S.2¢  of VI in lung adenocarcinoma and squamous cell carcinoma. In

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    Lung Cancer 82 (2013) 407– 412

    Contents lists available at ScienceDirect

    Lung Cancer

    j ourna l ho me page: www.elsev ier .com/ locate / lungcan

    ifferences in the prognostic implications of vascular invasion etween lung adenocarcinoma and squamous cell carcinoma

    hingo Usuia,b, Yuko Minamia,∗, Toshihiro Shiozawaa, Shinji Iyamaa, Kaishi Satomia, hingo Sakashitaa, Yukio Satob, Masayuki Noguchia

    Department of Pathology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba-shi, Ibaraki, 305-8575, Japan Department of Thoracic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba-shi, Ibaraki, 305-8575, Japan

    r t i c l e i n f o

    rticle history: eceived 1 July 2013 eceived in revised form 19 August 2013 ccepted 4 September 2013

    eywords: ascular invasion denocarcinoma eripheral-type squamous cell carcinoma arge-vessel invasion rognosis avity formation

    a b s t r a c t

    Objectives: Vascular invasion (VI) has been accepted as a universally important prognostic factor for patients with lung carcinoma. However, the clinical significance of VI in each of the histological subtypes has been unclear. The aim of the present study was to investigate differences in the clinicopathological implications of VI between adenocarcinoma and squamous cell carcinoma. Method: A total of 336 patients were evaluated, of whom 81 were diagnosed as having peripheral-type squamous cell carcinoma, and 255 as having adenocarcinoma. Result: Among the 336 patients, the five-year survival rates for those who were VI-positive and VI-negative were 38.4% and 76.3%, respectively, the difference being significant (p < 0.0001). Multivariate analysis identified VI as an independent prognostic factor (hazard ratio: 1.86). Although the difference in cancer- free survival between VI-positive and -negative patients was statistically significant for adenocarcinoma (p < 0.0001), it was not significant for squamous cell carcinoma (p = 0.086). For adenocarcinoma, the difference between the survival curves for VI-positive and -negative patients was significant for the sub- types with a predominant lepidic (p < 0.0001), papillary (p = 0.0026), and acinar (p = 0.0060) component,

    whereas that for the predominantly solid subtype was not significant (p = 0.58). Squamous cell carcino- mas were then divided into two groups on the basis of the diameter of vessels that had been invaded by the cancer cells: large-vessel invasion (LVI; 1000 �m or more) and small-vessel invasion (SVI; less than 1000 �m). Although there was no difference in the survival curves between the LVI and SVI groups, the LVI group showed a significantly higher incidence of cavity formation and distant metastasis. Conclusion: We conclude that VI is a useful prognostic indicator in lung carcinoma, although the clinical


    implications of VI differ b

    . Introduction

    Lung cancer is the leading cause of cancer-related death world- ide. Even for patients with pathological stage I lung cancer, the ve-year survival rate is approximately 66–83%, which is far from atisfactory [1]. Previously reported prognostic factors for patients ith lung cancer have included age, sex, performance status (PS), eripheral neutrophil and lymphocyte counts, tumor size, pleural

    nvasion, lymphatic permeation, vascular invasion (VI), lymph node etastasis, and distant metastasis [2–6]. Among them, old age,

    ale gender, poor PS, high neutrophil count, large tumor size, and

    resence of pleural invasion, lymphatic permeation, lymph node etastasis and distant metastasis are all indicative of an unfavor-

    ble prognosis. VI in particular has been accepted as an important

    ∗ Corresponding author. Tel.: +81 29 853 3150; fax: +81 29 853 3150. E-mail address: (Y. Minami).

    169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. ttp://

    en adenocarcinoma and squamous cell carcinoma. © 2013 Elsevier Ireland Ltd. All rights reserved.

    prognostic factor for patients with not only all stages [7–9] but also early-stage [10–15] lung cancers.

    Among the histological subtypes of lung cancer, a few reports have indicated that VI is prognostically significant in adeno- carcinoma. For example, Bodendorf et al. have reported that adenocarcinoma frequently shows distant metastasis rather than local recurrence, and that VI is more significantly associated with metastasis than with local recurrence, thus being an indi- cator of poor prognosis [9]. Using a logistic regression model, Ruffini indicated that the differences between adenocarcinoma with and without VI, and between adenocarcinoma and non- adenocarcinoma, were significant [15]. These previous reports suggested that VI is a unique prognostic indicator in individual

    patients. On the other hand, the contribution of VI to the outcome of squamous cell carcinoma has not been reported.

    In 2011, a new multidisciplinary classification of pulmonary adenocarcinoma was proposed [16]. In this classification, invasive adenocarcinoma was divided into five different subtypes, i.e. those

  • 408 S. Usui et al. / Lung Cancer 82 (2013) 407– 412

    Table 1 Clinicopathological characteristics of all patients (n = 336).

    All cases (n = 336) Ad (n = 255) Sq (n = 81)

    Age 69.0 ± 9.9 67.6 ± 10.3 73.4 ± 7.0 Sex (male/female) 225/111 153/102 72/9 Tumor Size (Av. ± S.D.) 28.0 ± 14.1 26.0 ± 12.6 34.1 ± 16.6 Primary site (left/right) 146/190 102/153 44/37 Surgical procedure (par/seg/lob/pn) 30/30/274/2 23/23/207/2 7/7/67/0 Pathological stage (IA/IB/IIA/IIB/IIIA/IIIB/IV) 131/86/32/30/47/2/8 106/60/25/16/39/1/8 25/26/7/14/8/1/0 Pathological T (1a/1b/2a/2b/3/4) 87/55/132/14/46/2 75/40/98/9/31/2 12/15/34/5/15/0 Pathological N (0/1/2/3) 254/37/44/1 189/29/37/0 65/8/7/1 Presence of distant metastasis (%) 16 (4.8%) 10 (3.9%) 6 (7.4%) Pleural invasion (0/1/2/3) 211/75/24/26 164/57/20/14 47/18/4/12 Presence of vascular invasion (%) 160 (47.6%) 115 (45.1%) 45 (55.6%) Presence of lymphatic permeation (%) 145 (43.2%) 114 (44.7%) 31 (38.3%) Recurrence of cancer (%) 99 (29.5%) 67 (26.3%) 30 (37.0%) Cause of death 82 (24.4%) 59 (23.1%) 23 (28.4%) Lung cancer 53 43 10

    p d, ade

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    F (

    Other 27 Unknown 2

    ar, partial resection; seg, segmentectomy; lob, lobectomy; pn, pneumonectomy; A

    ith a predominantly lepidic, acinar, papillary, micropapillary or olid component. These five subtypes differ not only histologi- ally, but also prognostically. Nakazato reported that tumors with

    predominant lepidic, acinar or papillary component had a more avorable prognosis than tumors with a predominant micropapil- ary or solid component [17]. However, the clinical implications of I in these various histological subtypes have not been analyzed.

    The aim of the present study was to confirm the clinical signifi- ance of VI in lung adenocarcinoma and squamous cell carcinoma. n addition, we examined the value of VI among the five histo- ogical subtypes of adenocarcinoma and the relationship between

    acroscopic cavity formation and VI in squamous cell carcinoma.

    . Materials and methods

    .1. Case selection

    Between January 2001 and December 2010, 420 consecutive atients with a histological diagnosis of adenocarcinoma or squa- ous cell carcinoma underwent surgical treatment at Tsukuba niversity Hospital (Ibaraki, Japan). Eighty-four patients who ad central-type squamous cell carcinoma (n = 14), preoperative reatment (n = 18), adenocarcinoma in situ, minimally invasive denocarcinoma and pure mucinous adenocarcinoma (n = 52) ere excluded, leaving a final total of 336 patients for inclusion

    n this study. In addition, as cases of adenosquamous carcinoma nd sarcomatoid carcinoma were very limited, these were also xcluded. From among these patients, we obtained 81 speci- ens of peripheral-type squamous cell carcinoma arising beyond

    he subsegmental bronchus, and 255 specimens of invasive

    ig. 1. Pathologic findings of vascular invasion (VI) in (a) adenocarcinoma and (b) squamo c) large-vessel invasion (LVI) by squamous cell carcinoma (EVG, ×2.5). Each black bar is

    16 11 0 2

    nocarcinoma; Sq, squamous cell carcinoma.

    adenocarcinoma; the patients’ clinical characteristics were obtained from the hospital’s database. All of the patients gave informed consent for study of their surgical materials before collection. The study was approved by the Regional Committee for Medical Research Ethics (University of Tsukuba). The patients’ clinicopathological profiles are summarized in Table 1.

    Preoperative assessment of the patients included chest and abdominal computed tomography (CT), bone scintigraphy, brain magnetic resonance imaging (MRI), and peripheral venous blood sampling for evaluation of tumor markers. CEA (ng/ml), SCC (ng/ml) and proGRP (pg/ml) were measured by ELISA. NSE (ng/ml) was measured by RIA, and CYFRA (ng/ml) and SLX (ng/ml) were mea- sured by IRMA. All markers were evaluated within a month before surgery. Patients in whom distant metastasis was detected within one month after surgery were recognized as havin