Histologic categorization of desmoplastic reaction: its relevance to the colorectal cancer microenvironment and prognosis.
BACKGROUND
Although the essential roles of stromata in tumor development have been recognized, the morphologic classification of desmoplastic reaction (DR) in colorectal cancer (CRC) is unclear.


METHODS
In this study, DRs were histologically classified into three patterns based on the products of activated fibroblasts (i.e., keloid-like collagen and myxoid stroma). The prognostic impact of DRs was evaluated in two independent cohorts of stages 2 and 3 CRC patients: cohort 1 (880 patients) and cohort 2 (474 patients). The association of DR and the local environment was investigated immunohistochemically.


RESULTS
In cohort 1, mature DR was shown by 413 patients, intermediate DR by 275 patients, and immature DR by 192 patients. Categorization of DR was significantly associated with tumor location, pT and pN stages, tumor differentiation, venous invasion, tumor budding, and Crohn's-like lymphoid reaction (P ≤ 0.0001-0.008). Immature DR was relevant to the high incidence of recurrence in the liver, lung, lymph nodes, peritoneum, and locoregional areas (P ≤ 0.0001-0.002). The 5-year disease-free survival rate was highest in the mature group (87 %), followed by the intermediate group (72 %) and the immature group (49 % (P < 0.0001). In the multivariate analysis, DR showed an impact on survival outcome independent of conventional prognostic factors, including pT and pN stages. These results were similarly observed in cohort 2. Immature DR was associated with normal MutL homologue 1 (MLH1)/MutS homologue 2 (MSH2) immunoreactivity, a smaller number of infiltrating CD8(+) T cells and tumor-associated macrophages, a decreased microvessel count, and positive expression of tenascin-C and fibronectin.


CONCLUSIONS
The proposed histologic DR categorization directly reflects tumor behavior in a modulating stromal environment and could provide valuable prognostic information for CRC patients.
Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan, ueno@ndmc.ac.jp.
Hideki
H
Ueno
Eiji
E
Shinto
Hideyuki
H
Shimazaki
Yoshiki
Y
Kajiwara
Takahiro
T
Sueyama
Junji
J
Yamamoto
Kazuo
K
Hase
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D003131:Combined Modality Therapy; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D005355:Fibrosis / Q000473:pathology*; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology*; D015996:Survival Rate; D059016:Tumor Microenvironment
D014408:Biomarkers, Tumor