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.

Family history, body mass index and survival in Japanese patients with stomach cancer: a prospective study.

Family history and nutritional status may affect the long-term prognosis of stomach cancer, but evidence is insufficient and inconsistent. To clarify the prognostic factors of stomach cancer, we conducted a prospective study of 1,033 Japanese patients with histologically confirmed stomach cancer who were admitted to a single hospital between 1997 and 2005. Family history of stomach cancer and pretreatment body mass index (BMI) were assessed using a self-administered questionnaire. Clinical data were retrieved from a hospital-based cancer registry. All patients were completely followed up until December, 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated according to family history in parents and siblings and BMI category. During a median follow-up of 5.3 years, 403 all-cause and 279 stomach cancer deaths were documented. Although no association with family history was observed in the patients overall, analysis according to age group found an increased risk of all-cause death associated with a history in first degree relatives (HR = 1.61, 95% CI: 0.93-2.78, p = 0.09) and with a parental history (HR = 1.86, 95% CI: 1.06-3.26) among patients aged under 60 years at diagnosis. BMI was related to all-cause and stomach cancer death among patients aged 60 and over, showing a J-shaped pattern (HR of all-cause death = 2.28 for BMI < 18.5; HR = 1.61 for 25 ≤ vs. ≥ 23.0 to < 25.0 kg/m(2)). A family history of stomach cancer, especially parental history, may affect mortality among younger stomach cancer patients, whereas nutritional status may be a prognostic factor in older patients.

Enhanced expression of long non-coding RNA HOTAIR is associated with the development of gastric cancer.

The long non-coding RNA HOTAIR has been reported to be a poor prognostic biomarker in a variety of malignant tumors. However, little is known about the association of HOTAIR with gastric cancer. We examined the expression of HOTAIR in 68 gastric cancer samples using quantitative real-time RT-PCR and analyzed its correlation with the clinical parameters. The functional role of HOTAIR was examined by generating human gastric cancer cell lines with increased or suppressed HOTAIR expression. The anchorage -independent growth was assessed by soft agar assay. The increased or suppressed HOTAIR expressing gastric cancer cells were injected into the tail vein or peritoneal cavity of immunodeficient mice to examine the effect of this molecule on metastasis and peritoneal dissemination. The expression of HOTAIR was significantly higher in cancer lesions than in adjacent non-cancerous tissues in human gastric cancers. In the diffuse type of gastric cancer, the High-HOTAIR group (HOTAIR/GAPDH > 1) showed significantly more venous invasion, frequent lymph node metastases and a lower overall survival rate compared to the Low-HOTAIR group (HOTAIR/GAPDH < 1). Colony formation on the soft agar was enhanced in a HOTAIR-dependent manner. HOTAIR-expressing MKN74 formed more liver metastasis compared to control when they were injected into the tail vein of mice. In addition, reduced expression of HOTAIR in KATO III suppressed peritoneal dissemination. These results suggest that HOTAIR plays a pivotal role in the development of gastric cancer.

[A case of pancreatic endocrine tumor developing from intraductal papillary mucinous neoplasm (IPMN)].

In March, 2004, a 64-year-old man was given a diagnosis of IPMN of the pancreas in postoperative CT of left shoulder blade chondrosarcoma. In October, 2007, because a tumor in the pancreas body was found, distal pancreatectomy was performed a diagnosis of the poorly differentiated adenocarcinoma. Histopathologic diagnosis revealed as pancreatic endocrine tumor and immunity dyeing was useful for differential diagnosis. A case of pancreatic endocrine tumor developing from IPMN has a possibility not rare for frequency, but few reports are available so far.

Human sialidase as a cancer marker.

Altered sialylation of cell surface glycoproteins and glycolipids is closely related to the malignant phenotype of cancer cells, including the metastatic potential and invasiveness. Many cancer-related antigens in clinical use contain sialic acids at the terminal position of sugar chains in the molecules. To elucidate the molecular mechanism, we focused our investigation on sialidase, which catalyzes the removal of sialic acid residues from the glycoconjugates. Four types of human sialidases identified to date behave in different manners during carcinogenesis. One of the sialidases, found in the lysosomes, showed downregulation in cancers, promoting anchorage-independent growth, and metastatic ability, while another, found in the plasma membrane, showed marked upregulation, causing apoptosis suppression. It was found that estimation of the mRNA levels of sialidases by real-time PCR allowed discrimination of cancerous from noncancerous tissues and even determination of the pathological stage in some cancers. Immunohistochemistry of cancer tissues using the antibody against the plasma membrane sialidase was useful for clinical diagnosis. This paper briefly summarizes our findings of the altered sialidase expression in cancers and the possibility of their clinical application as cancer markers. Human sialidases are indeed related to malignancy and may be potential targets for cancer diagnosis and therapy.

Down-regulation of sialidase NEU4 may contribute to invasive properties of human colon cancers.

In mammalian cells, four types of sialidase have been described and found to behave in different ways during carcinogenesis. We previously demonstrated that a human sialidase associated with plasma membranes (NEU3) is up-regulated in human colon cancer and is involved in suppression of apoptosis. Here we document altered expression of another human sialidase, the recently identified NEU4, and evidence of its influence on the malignant phenotype in colon cancers. Human colon mucosa was relatively rich in NEU4, which has been observed to possess short and long isoforms, but hardly contained the latter form. In clear contrast to the NEU3 case, the levels of mRNA for this sialidase were found by quantitative RT-PCR to be markedly decreased in colon cancers. In cultured human colon cancer cells, the enzyme was up-regulated in the early stage of apoptosis induced by either the death ligand TRAIL or serum-depletion, and transfection of NEU4 resulted in acceleration of apoptosis and in decreased invasion and motility. The siRNA-mediated NEU4 targeting, on the other hand, caused a significant inhibition of apoptosis and promotion of invasion and motility. Lectin blot analyses revealed that desialylated forms of nearly 100 kDa glycoproteins were prominently increased with PNA in NEU4 transfectants, whereas only slight changes in glycolipids were detected as assessed by thin layer chromatography. These results suggest that NEU4 plays important roles for maintenance of normal mucosa mostly through desialylation of glycoproteins and that down-regulation may contribute to invasive properties of colon cancers.

Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression.

Human plasma membrane-associated sialidase (Neu3) is unique in specifically hydrolyzing gangliosides, thought to participate in cell differentiation and transmembrane signaling, thereby playing crucial roles in the regulation of cell surface functions. We have discovered levels of mRNA for this sialidase to be increased in restricted cases of human colon cancer by 3- to 100-fold compared with adjacent nontumor mucosa (n = 32), associated with significant elevation in sialidase activity in tumors (n = 50). In situ hybridization showed the sialidase expression in epithelial elements of adenocarcinomas. In cultured human colon cancer cells, the sialidase level was down-regulated in the process of differentiation and apoptosis induced by sodium butyrate, whereas lysosomal sialidase (Neu1) was up-regulated. Transfection of the sialidase gene into colon cancer cells inhibited apoptosis and was accompanied by increased Bcl-2 and decreased caspase expression. Colon cancer exhibited a marked accumulation of lactosylceramide, a possible sialidase product, and addition of the glycolipid to the culture reduced apoptotic cells during sodium butyrate treatment. These results indicate that high expression of the sialidase in cancer cells leads to protection against programmed cell death, probably modulation of gangliosides. This finding provides a possible sialidase target for diagnosis and therapy of colon cancer.