Clinicopathological and molecular characterization of colorectal micropapillary carcinoma

Abstract

Invasive micropapillary carcinoma is associated with frequent lymph node metastasis and adverse clinical outcome. Initially described as a variant of breast and ovarian carcinoma, it has subsequently been found in other organs, most recently the colon. Reports of colorectal micropapillary carcinoma to date are limited in number, and their molecular profile has not been established. The aims of the present study were to analyze their clinicopathological features and molecular profile, and compare them with those of conventional adenocarcinoma. Clinicopathological features of a cohort of 379 patients with primary colorectal cancer were retrospectively reviewed for the presence of the pattern characteristic of micropapillary carcinoma. We also assessed the expression of KRT7, KRT20, CEACAM5, MUC1 (EMA, clone E29), MUC1 (clone MA695), MLH1, MSH2, MSH6 and TP53 by immunohistochemistry. Genetic assessments of microsatellite instability, chromosomes 17p and 18q, and mutations in TP53, BRAF and KRAS were performed using DNA extracted from formalin-fixed, paraffin-embedded sections. In all, 60 of the reviewed cases (16%) had a micropapillary component that ranged from 5 to 95% of the tumor, characterized by a higher frequency of an infiltrative pattern, lymphovascular and perineural invasion, a higher depth of invasion and more positive lymph nodes than conventional adenocarcinoma. Immunohistochemistry for MUC1 (clone MA695) and MUC1 (EMA, clone E29) enhanced the characteristic inside-out staining pattern of the micropapillary carcinoma component, whereas the rest of the tumor showed luminal staining patterns. KRT7 expression was slightly increased in micropapillary carcinoma, but did not reach significance (17-3%, P ¼ 0.1967). The molecular parameters showed a higher frequency of TP53 alterations and a low incidence of microsatellite instability and RER phenotype (loss of mismatch repair protein) in micropapillary carcinoma. With regard to the histological parameters, micropapillary carcinoma appears to be more aggressive than conventional colorectal adenocarcinoma. The molecular profile supports the hypothesis that micropapillary carcinoma carcinogenesis develops through the classical chromosomal instability pathway.

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

“…7 Several studies showed the prevalence of micropapillary carcinoma was 9-19% in colorectal carcinoma, and it was associated with aggressive histological features, including higher levels of lymphovascular invasion and perineural invasion, more frequent lymph node and distant metastases, and higher TNM stages (III/ IV). [8][9][10][11] In concordance with previous studies, we identified 10% of colorectal carcinoma with micropapillary carcinoma component from our cohort (55/561 cases), and micropapillary carcinoma was significantly associated with higher Figure 2 Kaplan-Meier survival analysis (log rank test). (a and b) Non-micropapillary carcinoma patients experience significantly better overall survival rates (Po0.0001, a) and disease-free survival rates (Po0.0001, b) than patients with micropapillary carcinoma.…”

“…Previous published studies found that the proportion of micropapillary carcinoma to the entire tumor ranged from 5 to 80%, and defined micropapillary carcinoma as carcinoma with at least 5% of micropapillary components. [8][9][10][11] On the other hand, as the identification of tumorinitiating cells, also referred to as cancer stem cells, in acute myeloid leukemia, their presence has also been identified in a number of solid tumor types, such as breast, lung, ovarian, brain, and colon cancer. [12][13][14][15][16][17] Emerging evidence suggests that stem cells have a crucial role not only in the embryonic development and maintenance of mature normal tissues, but also in the development of malignancies and disease progression associated with poor prognosis.…”

Colon cancer with micropapillary carcinoma component: a clinopathologic study of 9 cases

“…To date, the majority of reported cases are single case report [8,9,10,11,12,13,14,15]. However, there are only a few reports on a large scale clinicopathological study of colon cancer with MPP [16,17,18,19,20]. Although colon cancer with MPP behaves aggressively even in TNM Stage I and II, there is little evidence on the clinical outcome in this tumour [16].…”

Pure Micropapillary Rectal Carcinoma with CK7 and CK20 Coexpression and Loss of CDX2 Reactivity

“…Except for the ovary, micropapillary carcinoma arising in many organs seems to pursue an aggressive clinical course because of frequent invasion into lymphatic spaces, metastasis into lymph nodes, or systemic metastasis (Verdú et al;Amin et al, 2002;Amin et al, 1994;Nassar;Nassar et al;Paterakos et al;Siriaunkgul & Tavassoli;Zekioglu et al;Haupt et al;Kim et al;Kuroda et al;Sakamoto et al;Wen et al;Xu et al). Micropapillary carcinoma of the colon macroscopically seems to be indistinguishable from conventional adenocarcinoma.…”

“…The micropapillary carcinoma is regarded as an aggressive variant of adenocarcinoma in any location described, namely bladder, lung, pancreas, salivary glands and recently colon, rectum and stomach (Verdú et al, 2011;Amin et al, 2002;Amin et al, 1994;Nassar, 2004;Nassar et al, 2001;Paterakos et al, 1999;Siriaunkgul & Tavassoli, 1993;Zekioglu et al, 2004). Histologically is characterized by papillary cell clusters surrounded by clear spaces.…”