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Clinicopathological characteristics associated with necrosis in pulmonary metastases from colorectal cancer

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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.

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Funding

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

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Authors and Affiliations

  1. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Jun Suzuki, Motohiro Kojima, Takashi Sakai, Hiroshi Nakamura, Yuuki Ohara, Satoshi Fujii & Genichiro Ishii

  2. Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan

    Jun Suzuki, Keiju Aokage, Takashi Sakai, Kenta Tane, Tomohiro Miyoshi & Masahiro Tsuboi

  3. Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan

    Jun Suzuki, Hiroshi Nakamura & Kenji Suzuki

  4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan

    Yuuki Ohara, Masato Sugano & Takeshi Kuwata

  5. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan

    Atsushi Ochiai

  6. Department of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Masaaki Ito

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  1. Jun Suzuki
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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.

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Correspondence to Genichiro Ishii.

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The authors declare that they have no conflict of interest.

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This article is part of the Topical Collection on Quality in Pathology

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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)

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Suzuki, J., Kojima, M., Aokage, K. et al. Clinicopathological characteristics associated with necrosis in pulmonary metastases from colorectal cancer. Virchows Arch 474, 569–575 (2019). https://doi.org/10.1007/s00428-019-02535-7

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  • DOI: https://doi.org/10.1007/s00428-019-02535-7

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