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Clinicopathological characteristics associated with necrosis in pulmonary metastases from colorectal cancer

  • Jun Suzuki
  • Motohiro Kojima
  • Keiju Aokage
  • Takashi Sakai
  • Hiroshi Nakamura
  • Yuuki Ohara
  • Kenta Tane
  • Tomohiro Miyoshi
  • Masato Sugano
  • Satoshi Fujii
  • Takeshi Kuwata
  • Atsushi Ochiai
  • Masaaki Ito
  • Kenji Suzuki
  • Masahiro Tsuboi
  • Genichiro IshiiEmail author
Original Article
Part of the following topical collections:
  1. Quality in Pathology

Abstract

Metastatic lung cancers from the colon and rectum (MLCR) frequently have necrotic components. The aim of this study is to elucidate clinicopathological factors associated with the amount of necrosis in MLCR. Ninety patients who underwent the first pulmonary metastasectomy for MLCR with a tumor diameter ≦ 3.0 cm and without chemotherapy were enrolled in this study. Analyzing digitally scanned pathological slides, we calculated the necrosis percentage (NP, the necrosis area divided by the tumor area). The relationship between NP and clinicopathological factors was analyzed. Moreover, to determine whether NP was affected by tissue hypoxia, vascularization, or tumor cell proliferation, tissues were analyzed by immunohistochemical staining using carbonic anhydrase IX (CAIX), CD34 antibodies, and Ki-67 antibodies, respectively. Median tumor area and NP were 0.69 cm2 (0.11–3.01) and 13.1% (0–71.6), respectively. Although NP was not associated with the tumor area, it was significantly higher in the patients with a positive smoking history (8.14% vs 17.1%, p = 0.045). Other clinicopathological factors were not correlated with NP. Immunohistochemical analysis revealed that CA IX expression on tumor cells, CD34 micro-vessel density, CD34 micro-vessel area, and Ki-67 index were not significantly associated with NP. NP in the primary site was not associated with NP in the pulmonary metastasis. NP was not determined by tumor size, tissue hypoxia, vascularization, or tumor cell proliferation. Positive correlation of NP with smoking history suggests a unique lung microenvironment in smokers which makes necrosis of MLCR more likely to occur.

Keywords

Colorectal cancer Pulmonary metastasis Pathology Necrosis 

Notes

Author contributions

JS and GI contributed to the design and organization and conducted the study and wrote the manuscript. TS and HN helped in the immunohistochemical process and created the pathological database. MK, YO, MS, MF, TK, AO, and KS advised the direction of study and the interpretation of the data. KA, KT, TM, MI, and MT contributed to provide surgical samples and clinical data. All the authors reviewed and accepted the manuscript.

Funding

This work was supported in part by JSPS KAKENHI (16H05311).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2019_2535_MOESM1_ESM.pptx (27.6 mb)
Supplementary Figure 1 The examples of actual measurement of the tumor area and necrosis in MLCR with massive necrosis (A) and multiple necrosis (B). The tumor area and the necrosis area were measured by circumscribing the whole tumor area (black line) and necrosis area (red line) on the image-analyzing software (NDP.view2). The values of the automatically calculated areas were shown in the yellow boxes. In the case of multiple necroses, we included as many areas of necrosis areas as possible. Supplementary Fig. 2. The image analysis of the CD34 (A, B) and Ki-67 (C, D) immunohistochemical staining using ImageScope. Each hot spot was 50 μm2 (shown in green line). Each CD34 positive vessels in the hotspot is marked as a green area (B). The number of vessels and vessel area were calculated as MVD and MVA, respectively. In Ki67 index analysis, non-tumor cells were excluded by the dotted line (C). Cells negative, 1+, and 2+ for Ki-67 were marked as blue, yellow, and orange, respectively (D). Supplementary Fig. 3. The scatter plots showing the positive relationship between necrosis percentage and tumor diameter (A) or tumor area (B) in the primary sites. Supplementary Fig. 4. Comparison of the necrosis percentage between patients who had surgery alone and patients who had preoperative chemotherapy and surgery for lung metastases. Supplementary Fig. 5. Comparison of Kaplan-Meier curves for the recurrence free survival and the overall survival between the patients with high and low necrotic percentage. (PPTX 28280 kb)

References

  1. 1.
    GLOBOCAN, International Agencyfor Research on Cancer, WHO. Cancer today: estimated number of incident cases, both sexes, Worldwide (Top 10 Cancer Sites) in 2012. 2018Google Scholar
  2. 2.
    Inoue M, Ohta M, Iuchi K, Matsumura A, Ideguchi K, Yasumitsu T, Nakagawa K, Fukuhara K, Maeda H, Takeda S, Minami M, Ohno Y, Matsuda H, Thoracic Surgery Study Group of Osaka University (2004) Benefits of surgery for patients with pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 78(1):238–244CrossRefGoogle Scholar
  3. 3.
    Rama N, Monteiro A, Bernardo JE, Eugénio L, Antunes MJ (2009) Lung metastases from colorectal cancer: surgical resection and prognostic factors. Eur J Cardiothorac Surg 35(3):444–449CrossRefGoogle Scholar
  4. 4.
    Marchevsky AM, Gupta R, Balzer B (2010) Diagnosis of metastatic neoplasms: a clinicopathologic and morphologic approach. Arch Pathol Lab Med 134(2):194–206Google Scholar
  5. 5.
    Flint A, Lloyd RV (1992) Pulmonary metastases of colonic carcinoma. Distinction from pulmonary adenocarcinoma. Arch Pathol Lab Med 116(1):39–42Google Scholar
  6. 6.
    Caruso RA et al (2014) Mechanisms of coagulative necrosis in malignant epithelial tumors (review). Oncol Lett 8(4):1397–1402CrossRefGoogle Scholar
  7. 7.
    Weidner N (1999) Tumour vascularity and proliferation: clear evidence of a close relationship. J Pathol 189(3):297–299CrossRefGoogle Scholar
  8. 8.
    Vayrynen SA et al (2016) Clinical impact and network of determinants of tumour necrosis in colorectal cancer. Br J Cancer 114(12):1334–1342CrossRefGoogle Scholar
  9. 9.
    Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60(5):1388–1393Google Scholar
  10. 10.
    Pollheimer MJ, Kornprat P, Lindtner RA, Harbaum L, Schlemmer A, Rehak P, Langner C (2010) Tumor necrosis is a new promising prognostic factor in colorectal cancer. Hum Pathol 41(12):1749–1757CrossRefGoogle Scholar
  11. 11.
    Richards CH, Roxburgh CSD, Anderson JH, McKee RF, Foulis AK, Horgan PG, McMillan DC (2012) Prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer. Br J Surg 99(2):287–294CrossRefGoogle Scholar
  12. 12.
    Swinson DE et al (2002) Tumour necrosis is an independent prognostic marker in non-small cell lung cancer: correlation with biological variables. Lung Cancer 37(3):235–240CrossRefGoogle Scholar
  13. 13.
    Pichler M, Hutterer GC, Chromecki TF, Jesche J, Kampel-Kettner K, Rehak P, Pummer K, Zigeuner R (2012) Histologic tumor necrosis is an independent prognostic indicator for clear cell and papillary renal cell carcinoma. Am J Clin Pathol 137(2):283–289CrossRefGoogle Scholar
  14. 14.
    Loupakis F, Schirripa M, Caparello C, Funel N, Pollina L, Vasile E, Cremolini C, Salvatore L, Morvillo M, Antoniotti C, Marmorino F, Masi G, Falcone A (2013) Histopathologic evaluation of liver metastases from colorectal cancer in patients treated with FOLFOXIRI plus bevacizumab. Br J Cancer 108(12):2549–2556CrossRefGoogle Scholar
  15. 15.
    Ishida K, Uesugi N, Hasegawa Y, Sugimoto R, Takahara T, Otsuka K, Nitta H, Kawasaki T, Wakabayashi G, Sugai T (2015) Proposal for novel histological findings of colorectal liver metastases with preoperative chemotherapy. Pathol Int 65(7):367–373CrossRefGoogle Scholar
  16. 16.
    Wicherts DA, de Haas RJ, Sebagh M, Saenz Corrales E, Gorden DL, Lévi F, Paule B, Azoulay D, Castaing D, Adam R (2011) Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. Br J Surg 98(3):399–407CrossRefGoogle Scholar
  17. 17.
    Ng JK et al (2008) Colorectal liver metastases contract centripetally with a response to chemotherapy: a histomorphologic study. Cancer 112(2):362–371CrossRefGoogle Scholar
  18. 18.
    Paget S (1989) The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev 8(2):98–101Google Scholar
  19. 19.
    McCrea KA, Ensor JE, Nall K, Bleecker ER, Hasday JD (1994) Altered cytokine regulation in the lungs of cigarette smokers. Am J Respir Crit Care Med 150(3):696–703CrossRefGoogle Scholar
  20. 20.
    Kuschner WG, D'Alessandro A, Wong H, Blanc PD (1996) Dose-dependent cigarette smoking-related inflammatory responses in healthy adults. Eur Respir J 9(10):1989–1994CrossRefGoogle Scholar
  21. 21.
    Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8(12):1369–1375CrossRefGoogle Scholar
  22. 22.
    Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10(11):1349–1355CrossRefGoogle Scholar
  23. 23.
    Yahagi M, Tsuruta M, Hasegawa H, Okabayashi K, Toyoda N, Iwama N, Morita S, Kitagawa Y (2017) Smoking is a risk factor for pulmonary metastasis in colorectal cancer. Color Dis 19(9):O322–O328CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jun Suzuki
    • 1
    • 2
    • 3
  • Motohiro Kojima
    • 1
  • Keiju Aokage
    • 2
  • Takashi Sakai
    • 1
    • 2
  • Hiroshi Nakamura
    • 1
    • 3
  • Yuuki Ohara
    • 1
    • 4
  • Kenta Tane
    • 2
  • Tomohiro Miyoshi
    • 2
  • Masato Sugano
    • 4
  • Satoshi Fujii
    • 1
  • Takeshi Kuwata
    • 4
  • Atsushi Ochiai
    • 5
  • Masaaki Ito
    • 6
  • Kenji Suzuki
    • 3
  • Masahiro Tsuboi
    • 2
  • Genichiro Ishii
    • 1
    Email author
  1. 1.Division of Pathology, Exploratory Oncology Research and Clinical Trial CenterNational Cancer Center 6-5-1KashiwaJapan
  2. 2.Department of Thoracic SurgeryNational Cancer Center Hospital EastChibaJapan
  3. 3.Department of General Thoracic SurgeryJuntendo University School of MedicineTokyoJapan
  4. 4.Department of Pathology and Clinical LaboratoriesNational Cancer Center Hospital EastChibaJapan
  5. 5.Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterChibaJapan
  6. 6.Department of Colorectal SurgeryNational Cancer Center Hospital EastKashiwaJapan

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