Cutaneous metastasis of cancer is rare, occurring in 0.7%–5% of cancer patients . Higher rates of cutaneous metastasis occur in melanomas, breast and lung cancers, and mucosal carcinomas of the head and neck . The incidence of cutaneous metastasis of CRC is only 2.3% . Furthermore, there are few reports on the genetic background of cutaneous metastasis of CRC. The most common site of cutaneous metastasis in CRC is the abdominal skin, often on surgical incision scars. Other cutaneous sites include the pelvis, back, chest, upper extremities, head, and neck . The exact mechanisms of cutaneous metastasis are still unknown; however, four categories of mechanisms have been reported including the direct extension of primary cancer, lymphatic or hematogenous spread, and surgical implantation . Identification of cutaneous metastasis indicates a poor prognosis. The average survival of patients after the diagnosis of cutaneous metastasis of colon carcinoma is 18 months. In cases of multiple metastases or unresectable lesions, chemotherapy could be considered. When the lesion is resectable and painful, local excision is the preferred treatment option.
MSI is a genetic change caused by a deficiency in mismatch repair (MMR) systems. MSI-high is present in approximately 15% of patients with CRC . MSI-high is more common among those with stage II (20.2%) and stage III CRC (10.9%)  but is less frequent among those with stage IV CRC (3.5%) . MSI-high CRC is associated with better survival, right-sided primary tumors, and poorly differentiated tumors with mucinous histological feature . Another report showed that MSI-high CRC is diagnosed at a younger age and has fewer metastases to the liver and lungs than microsatellite stable (MSS) CRC . The most frequent site of metastasis in MSI-high CRC is the perineum (43.8%), followed by the liver (22.9%) and distant lymph nodes (18.8%) . To the best of our knowledge, this is the first report of cutaneous metastasis of MSI-high CRC. MSI-high tumors are heavily infiltrated by activated cytotoxic T-cell lymphocytes and Th1 lymphocytic cells . Pages et al. showed that compared with tumors with vascular emboli and lymphatic and perineural invasion, tumors without these early steps of the metastatic processes had increased infiltration of immune cells . These facts suggest that lymphocytic infiltration may make MSI-high CRC less likely to have distant metastases. There is greater immunoreactivity in deficient mismatch repair tumors 11,12,13] in stage II/III CRC; therefore, patients with MSI-high tumors have a better 5-year overall survival rate than those with MSS or MSI-low tumors . A previous study showed that lymphocyte infiltration into primary tumors is a strong independent predictor of relapse and overall survival, with high lymphocyte infiltration being a positive prognostic factor in CRC . A Buckowitz et al. reported that MSI-high CRCs with Crohn’s-like lymphocytic reaction are associated with fewer distant metastases . In this case, since there is neither high lymphocyte infiltration nor Crohn’s-like lymphocytic reaction, it may have led to distant metastases. In contrast, MSI-high is a poor prognostic factor in stage IV CRC [17, 18]. Compared with MSS or MSI-low CRCs, MSI-high CRC has the lowest rate of liver metastases and the highest rate of peritoneal metastases, which are related to prognosis . Tran et al. reported that BRAF mutant CRCs were observed to have significantly poorer survival compared with BRAF wild CRCs in MSI-high CRCs . BRAF mutations may contribute to the poor prognosis of stage IV MSI-high CRC.
BRAF is an RAS-regulated serine/threonine kinase in the RAS/RAF/MEK/ERK mitogen-activated protein kinase (M) signaling pathway, which governs proliferation, differentiation, migration, and apoptosis. BRAF mutations are found in approximately 5% of patients with metastatic CRC in our country  and 34.6% with MSI-high CRC . BRAF mutation is considered a poor prognostic factor. The most frequent site of metastasis in BRAF-mutant CRC is the liver (63%), followed by distant lymph nodes (56%) and the perineum (46%) . Lianggong et al. reported the first case of cutaneous metastases of BRAF-mutant CRC . In this case, FOLFIRI (irinotecan, calcium leucovorin, and 5-FU) in combination with cetuximab and the BRAF inhibitor vemurafenib caused cutaneous and liver metastases to shrink.
Pembrolizumab  and nivolmab + ipilimumab  have been confirmed to be effective treatments for MSI-high mCRC. In the KEYNOTE-177 study, pembrolizumab improved progression-free survival in patients with MSI-high metastatic CRC compared with the current chemotherapy regimen for first-line treatment of MSI-high metastatic CRC . For BRAF-mutant metastatic CRC, FOLFOXIRI + bevacizumab was reported as the first-line chemotherapy in the subgroup analysis of the TRIBE study . Furthermore, the effectiveness of the triple therapy of encorafenib, cetuximab, and binimetinib is reported . Chemotherapy including BRAF inhibitors is expected to treat CRC with distant metastases. However, it is unclear whether chemotherapy for BRAF mutations or chemotherapy for high MSI is prioritized for distant metastases with BRAF-mutant and MSI-high CRC. That is the research task hereafter. In our case, XELOX + bevacizumab combination was selected as the treatment because of her poor performance status and based on the domestic drug approval status. It could be one of the treatment options for BRAF-mutant and MSI-high CRC, because the therapeutic effect was confirmed.
We encountered a rare case of cutaneous metastasis of CRC that had MSI-high and a BRAFV600E mutation. In future, it will be necessary to accumulate more cases to identify clinical features and more effective treatments for cutaneous metastatic CRC.