Multiple distant metastases arising from a single, low-grade rectal neuroendocrine tumor: an autopsy case report.

BACKGROUND: Rectal neuroendocrine neoplasms are rare epithelial neoplasms of the rectum. The incidence of these tumors has increased over the past decades. However, many questions remain unanswered regarding their clinicopathology, including the possible mechanisms in which these tumors may grow and metastasize. CASE PRESENTATION: In this case report, we report the findings of an autopsy of a 65-year-old Japanese woman diagnosed with multiple liver metastases from a single, low-grade rectal neuroendocrine tumor. The diagnosis was made in late 2018 to early 2019, and subsequently the patient underwent several rounds of standard chemotherapy. However, due to unfavorable side effects, she opted for palliative care at our hospital instead from December 2020. The patient's condition was generally stable for the next 17 months, but in May 2022, she was hospitalized for increased abdominal pain. Despite enhanced pain control therapy, she eventually passed away. An autopsy was conducted to determine the exact cause of death. The primary rectal tumor was found to be small, but showed strong histological evidence of venous invasion. Metastases in the liver, pancreas, thyroid gland, adrenal glands, and vertebrae were also present. On the basis of the histological evidence obtained, we deduced that the tumor cells may have mutated and gained multiclonality as they spread vascularly to the liver, contributing to the distant metastases. CONCLUSIONS: The results from this autopsy may provide an explanation for the possible mechanism by which small, low-grade rectal neuroendocrine tumors metastasize.

[Mucinous Cystadenocarcinoma with a Sarcomatous Component Arising from the Sigmoid Mesocolon-A Case Report].

A 53‒year‒old female was referred to our hospital for abdominal pain. A cystic tumor evolving since 12 years, which was suspected of being a lymphocyst, was detected in her left lower abdomen. Computed tomography(CT)revealed the cystic tumor with enhanced 80 mm enlarged regions. Regarding the laboratory data, inflammatory parameters and tumor markers such as CA19‒9, CEA, and CA125 were elevated. Mucinous cystadenocarcinoma was highly suspected and a surgery was performed. Laparotomy showed that the tumor was located in the sigmoid mesocolon and there were multiple peritoneal disseminations. The tumor could not be separated from the sigmoid colon; therefore, tumor resection with partial sigmoidectomy was performed. The resected specimens showed mucus and solid lesions in the cystic tumor. The pathological findings revealed that the cystic tumor from the sigmoid mesocolon was a mucinous cystadenocarcinoma with large spindle‒ shaped atypical cells, which were considered to have undergone sarcomatous changes. No cases of mucinous cystadenocarcinoma with sarcoma arising from the sigmoid mesocolon have been previously reported. The prognosis of mucinous cystic neoplasm with sarcoma is suspected to be very poor, and the accumulation of such cases could help in improving their treatment.

[A Case of HER2 Positive Gastric Cancer That Was Highly Responsive to Fifth-Line Chemotherapy with Trastuzumab].

A 76-year-old male underwent distal gastrectomy for gastric cancer and pathological findings showed Stage Ⅳ(T4a, N3a, M1, H0, P0, CY1)with HER2 positivity. He received chemotherapy with S-1 and oxaliplatin(SOX)plus trastuzumab and no disease progression was shown. However, because of Grade 3 adverse skin effects to S-1, he could not continue with the regimen. He switched to a regimen of ramucirumab plus paclitaxel, followed by nivolumab, and later irinotecan. However, the disease progressed and multiple lung metastases as well as a left adrenal metastasis appeared. Fifth-line chemotherapy with trastuzumab was administered. After 4 courses, the lung metastases reduced and the left adrenal metastasis shrank from 46 mm to 33 mm. These results were consistent with a partial response on the Response Evaluation Criteria in Solid Tumors. In addition, CEA and CA19-9 also decreased significantly. Unfortunately, after 10 courses, the patient's disease progressed.

[Two Cases of Locally Advanced Colorectal Cancer Involving Pathological Complete Response after Chemotherapy].

We report 2 cases of locally advanced colorectal cancer in which complete response(CR)was achieved after chemotherapy. Case 1 involved a 71-year-old male diagnosed with rectal cancer invading the bladder. Chemotherapy with SOX plus bevacizumab and IRIS plus bevacizumab was administered for rectal cancer. Post-chemotherapy, the disease showed clinical CR(cCR)according to the Response Evaluation Criteria in Solid Tumors(RECIST). A laparoscopic abdominoperineal resection was then performed, with pathological findings showing no viable cancer cells. Eleven months postoperatively, the patient remains alive without disease recurrence. Case 2 involved a 54-year-old female diagnosed with a peritoneal abscess resulting from perforated sigmoid colon cancer. She received chemotherapy with SOX plus bevacizumab. Post-chemotherapy, the disease showed cCR according to the RECIST. A sigmoidectomy was performed, with pathological findings showing no viable cancer cells. Ten months postoperatively, the patient remains alive without disease recurrence. We believe that neoadjuvant chemotherapy is a feasible treatment option for locally advanced colorectal cancer.

[Two Cases of Resectable Liver Metastasis from Colorectal Cancer with Pathological Complete Response after Neoadjuvant Chemotherapy].

A 57-year-old male, who had received a laparoscopic low anterior resection for rectal cancer 12 months ago, was diagnosed a resectable liver metastasis from rectal cancer by computed tomography(CT). Neoadjuvant chemotherapy with mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab was performed for liver metastasis. After neoadjuvant chemotherapy, partial response(PR)was proved on the Response Evaluation Criteria in Solid Tumors(RECIST)and partial resection of the liver was conducted. Pathological findings showed no viable cancer cells. He is alive without recurrence 5 years after the surgery. A 70-year-old female, who had received a laparoscopic high anterior resection for rectal cancer 17 months ago, was diagnosed a resectable liver metastasis from rectal cancer by CT. SOX plus bevacizumab was performed for liver metastasis. After neoadjuvant chemotherapy, PR was proved on the RECIST and right hepatic lobectomy was performed. Pathological findings showed no viable cancer cells and she is alive without recurrence 4 years after the surgery. We expected neoadjuvant chemotherapy for resectable liver metastasis might be an option of treatment.

Steroid sulfatase and estrogen sulfotransferase in colon carcinoma: regulators of intratumoral estrogen concentrations and potent prognostic factors.

Previous epidemiologic and in vitro studies have indicated a potential involvement of estrogens in the pathogenesis of human colon carcinoma, but the precise roles of estrogens have remained largely unknown. Therefore, in this study, we first measured intratumoral concentrations of estrogens in 53 colon carcinomas using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS). Tissue concentrations of total estrogen [estrone (E(1)) + estradiol] and E(1) were significantly (2.0- and 2.4-fold, respectively) higher in colon carcinoma tissues than in nonneoplastic colonic mucosa (n = 31), and higher intratumoral concentrations of total estrogen and E(1) were significantly associated with adverse clinical outcome. Intratumoral concentration of total estrogen was significantly associated with the combined status of steroid sulfatase (STS) and estrogen sulfotransferase (EST), but not with that of aromatase. Thus, we subsequently examined the STS/EST status in 328 colon carcinomas using immunohistochemistry. Immunoreactivities for STS and EST were detected in 61% and 44% of the cases, respectively. The -/+ group of the STS/EST status was inversely associated with Dukes' stage, depth of invasion, lymph node metastasis, and distant metastasis and positively correlated with Ki-67 labeling index of the carcinomas. In addition, this -/+ group had significantly longer survival, and a multivariate analysis revealed the STS/EST status as an independent prognostic factor. Results from our present study showed that the STS/EST status of carcinoma tissue determined intratumoral estrogen levels and could be a significant prognostic factor in colon carcinoma, suggesting that estrogens are locally produced mainly through the sulfatase pathway and play important roles in the progression of the disease.

Bile acids repress E-cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma.

Although some kinds of bile acids have been implicated in colorectal cancer development, the mechanism of cancer progression remains unexplored in hepatobiliary cancer. From our personal results using complementary DNA microarray, we found that chenodeoxycholic acid (CDCA) induced Snail expression in human carcinoma cell lines derived from hepatocellular carcinoma and cholangiocarcinoma. Snail expression plays an important role in the regulation of E-cadherin and in the acquisition of invasive potential in many types of human cancers including hepatocellular carcinoma. We found that CDCA and lithocholic acid (LCA) induced Snail expression in a concentration-dependent manner and down-regulated E-cadherin expression in hepatocellular carcinoma and cholangiocarcinoma cell lines. Moreover, Snail short interference RNA (siRNA) treatment reduced the down-regulation of E-cadherin by CDCA or LCA. Luciferase analysis demonstrated that the promoter region from -111 to -24 relative to the transcriptional start site was necessary for this induction and, at least in part, nuclear factor Y (NF-Y) and stimulating protein 1 (Sp1) might be an inducer of Snail expression in response to bile acids. In addition, using an in vitro wound healing assay and invasion assay, we observed that CDCA and LCA induced cell migration and invasion. These results suggest that bile acids repress E-cadherin through the induction of transcription factor Snail and increase cancer invasiveness in human hepatocellular carcinoma and cholangiocarcinoma. Inhibition of this bile acid-stimulated pathway may prove useful as an adjuvant in the therapy of hepatocellular carcinoma.

Peroxisome proliferator-activated receptor alpha activates cyclooxygenase-2 gene transcription through bile acid transport in human colorectal cancer cell lines.

BACKGROUND: Evidence is accumulating that bile acids are involved in colon cancer development, but their molecular mechanisms remain unexplored. Bile acid has been reported to be associated with induction of the cyclooxygenase-2 (COX-2) gene. Because the human liver-specific organic anion transporter-2 (LST-2/OATP8/OATP1B3) is expressed in gastrointestinal cancers and might transport bile acids to the intracellular space, we studied the molecular mechanisms by which bile acids induce the transcription of COX-2, and the role of LST-2 in colonic cell lines. METHODS: Transcriptional activity of COX-2 was measured using a human COX-2 promoter-luciferase assay under various concentrations of bile acids. Electrophoresis mobility shift assays (EMSAs) for peroxisome proliferators-activated receptor (PPAR) alpha and cyclic AMP responsive element (CRE) were performed. RESULTS: The COX-2 promoter was induced by lithocholic acid (LCA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA). Deletion and site-directed mutation analyses showed that CRE is the responsive element for LCA. An adenovirus expression system revealed that LST-2 is responsible for induction of COX-2. By EMSA using oligonucleotides of CRE, we observed formation of a specific protein-DNA complex, which was inhibited by a specific antibody against PPARalpha and CRE. A PPARalpha-specific agonist induced transcription of COX-2. CONCLUSION: These results indicate that COX-2 is transcriptionally activated by the addition of LCA, CDCA, and DCA and that LST-2 plays an important role by transporting bile acid to the intracellular space. Moreover, LCA-dependent COX-2 gene activation consists of a transcriptional complex including PPARalpha and CRE-binding protein. Thus, this induction of COX-2 may participate in carcinogenesis and progression of colorectal cancer cells.