Colorectal Neuroendocrine Carcinomas Research Articles

Evaluation of association between center colorectal neuroendocrine neoplasm volume and survival among patients with colorectal neuroendocrine carcinoma.

Although correlation between center volume and survival has been reported for several complex cancers, it remains unknown if this is true for colorectal neuroendocrine carcinomas (CRNECs). We hypothesized that higher center annual volume of colorectal neuroendocrine neoplasm resections would be associated with overall survival (OS) for patients with CRNECs. Patients in the National Cancer Database diagnosed with stages I-III CRNEC between 2006 and 2018 and who underwent surgical resection were identified. The mean annual colorectal neuroendocrine neoplasm resection volume threshold associated with significantly worse mortality hazard was determined using restricted cubic splines. Kaplan-Meier (KM) method was used to compare OS, while Cox proportional hazards model was used for multivariable analysis. There were 694 patients with CRNEC who met inclusion criteria across 1229 centers. Based on the cubic spline, centers treating fewer than one colorectal neuroendocrine neoplasm patient every 3 years on average had worse outcomes. Centers below this threshold were classified as low-volume (LV) centers corresponding with 42% of centers and about 15% of the patient cohort. In unadjusted survival analysis, LV patients had a median OS of 14 months (95% confidence interval [CI]: 10-19) while those treated at HV centers had a median OS of 33 months (95% CI: 25-49). In multivariable analysis, resection at a LV center was associated with increased risk of mortality (1.42 [95% CI: 1.01-2.00], p = 0.04). CRNEC patients have a dire prognosis; however, treatment at an HV center may be associated with decreased risk of mortality.

Colorectal neuroendocrine carcinoma and mixed neuroendocrine-non-neuroendocrine neoplasm: Prognostic factors and PD-L1 expression

Colorectal neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) are rare malignancies with unclear boundaries and poor prognoses. Our study aimed to conduct a comparative analysis of these diseases, identify prognostic factors, and explore potential therapeutic targets. We collected and analyzed clinicopathological data of NEC and MiNEN in our hospital from 2011 to 2020. Immunohistochemical staining for PD-L1, BRAF V600E, and mismatch repair proteins was performed. We identified 14 NEC and 7 MiNEN cases. Demographic data, including median overall survival (17.1 months for NEC and 18.5 months for MiNEN), did not significantly differ. NEC showed a higher tendency to occur in the rectum and sigmoid colon (p = 0.025) and had fewer cases with metastatic adenocarcinoma components in lymph nodes (p = 0.009) compared to MiNEN. Adverse prognostic factors were age ≥70 years (p = 0.012), N2 nodal status (p = 0.032), and stage IV disease (p = 0.013) based on multivariate Cox regression analysis. We identified five PD-L1 positive cases, two BRAF V600E mutated cases, and one Lynch syndrome case with MSH2 and MSH6 loss. Patients with colorectal NEC or MiNEN exhibited poor survival rates. Adverse prognostic factors included older age, N2 nodal status, and distant metastasis. Potential therapeutic avenues such as immune checkpoint and BRAF inhibitors were suggested for patients with these carcinomas.

Establishment and validation of a prognostic nomogram for patients with colorectal neuroendocrine carcinoma

BackgroundColorectal neuroendocrine carcinoma is a relatively rare tumor, for which a prognosis prediction model is lacking. Based on the data from Surveillance, Epidemiology, and End Results (SEER) database and Fujian Cancer Hospital, the study constructed and validated a prognostic nomogram to assess overall survival of patients with colorectal neuroendocrine carcinoma(CRNEC). MethodsWe extracted data of patients diagnosed with CRNEC from the SEER database. These patients were randomly divided into a training cohort(N = 1425) and an internal validation cohort(N = 612). Data of patients diagnosed with CRNEC in Fujian Cancer Hospital was collected as an external validation cohort(N = 54). A prognostic nomogram was established. The performance of the nomogram was assessed with ROC curve, C-index and calibration curve. Decision curve analysis(DCA) and ROC curve were used to compare the prediction efficacy of nomogram with the seventh edition of the TNM classification of the American Joint Commission of Cancer. ResultsNine variables were identified as independent predictors. Nomogram were established by the nine variables. AUC of the nomogram in predicting 1-, 3- and 5-year OS were 0.900, 0.912 and 0.915 in training cohort, 0.900, 0.925 and 0.919 in internal validation cohort, 0.900, 0.903 and 0.928 in external validation cohort. C-index were 0.845, 0.854 and 0.837. Calibration curves overlapped well with reference lines. Compared with the AJCC TNM staging system, the nomogram performed more effectively. Patients classified into low-risk and high-risk groups by the nomogram scores and performed well in stratification. ConclusionThe prognostic nomogram established and validated in our study can accurately and effectively predict the prognosis of patients with CRNEC.

P373 An Unusual Occurrence of Right-sided Colonic Neuroendocrine Carcinoma in Ulcerative Colitis – A case report

Abstract Background It's estimated that inflammatory bowel disease (IBD) accounts for 1-2% of all colorectal cancer (CRC) cases. However, the mere presence of IBD increases the risk by 2 folds compared with the general population. It's been established that the most prevalent epithelial colonic malignancy linked to IBD is adenocarcinoma. Neuroendocrine neoplasms arising in the large intestines are extremely rare (rate <1%), even less common in association with IBD.(1) Herein, we report a 49 years-old male with a longstanding history of ulcerative pancolitis, who was found to have a metastatic right-sided colorectal neuroendocrine carcinoma (NEC). Methods Case Presentation A 49-years-old male patient, with a 13-years history of ulcerative pancolitis underwent a colonoscopy. It revealed a large ulcerated mass extending from the ileocecal valve into the proximal ascending colon highly suspicious for malignancy. Biopsy showed a large cell poorly differentiated NEC in the ascending colon. Tumor cells were positive for Synaptophysin and cytokeratin AE1/3, and a high Ki67. Serum Chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid were high. Imaging was evident for a short segment circumferential wall thickening at the ascending colon and hepatic metastasis. The patient was planned to receive chemotherapy, but died before treatment. Results Discussion Risk of CRC increments linearly approximately 7 years following diagnosis of IBD. After 30 years of colitis, the incidence is estimated to be around 18%. NECs in particular are not frequently encountered in association with IBD, much less right-sided.(1) Colonic NECs are usually aggressive with a Ki67 typically greater than 20%, often present with metastasis with absence of a characteristic hormonal secretion picture.(2, 3) The incidence of NECs in association with Ulcerative Colitis (UC) is twice more frequent in males, with a mean age of 49.36, and development after a median of 15 years of UC first diagnosis. Majority of NECs were found in the left side of the colon, in the contrary to our patient. Prognosis was dismal in most cases, as most demonstrated a higher malignant potential compared to adenocarcinomas.(3) Early diagnosis of gastrointestinal NECs poses a challenge since it lacks a specific clinical presentation. Serum CgA level correlates with the tumor burden and overall survival. Additionally, studies demonstrating the role of endoscopic surveillance in colonic NECs early detection is scarce.(1,4) Conclusion Thorough understanding of the condition and its risk factors is crucial for a timely diagnosis, which maximizes the likelihood of a favorable prognosis. By reporting this case, we emphasize the importance of considering NEC as a differential diagnosis of CRC in IBD, particularly in UC patients.

GATA3 Expression in Human Tumors: A Tissue Microarray Study on 16,557 Tumors

Introduction: GATA3 is a transcription factor involved in epithelial cell differentiation. GATA3 immunostaining is used as a diagnostic marker for breast and urothelial cancer but can also occur in other neoplasms. Methods: To evaluate GATA3 in normal and tumor tissues, a tissue microarray containing 16,557 samples from 131 different tumor types and subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: GATA3 positivity was found in 69 different tumor types including 23 types (18%) with at least one strongly positive tumor. Highest positivity rates occurred in noninvasive papillary urothelial carcinoma (92–99%), lobular carcinoma (98%), carcinoma of no special type of the breast (92%), basal cell carcinoma of the skin (97%), invasive urothelial carcinoma (73%), T-cell lymphoma (23%), adenocarcinoma of the salivary gland (16%), squamous cell carcinoma of the skin (16%), and colorectal neuroendocrine carcinoma (12%). In breast cancer, low GATA3 staining was linked to high pT stage (p = 0.03), high BRE grade (p < 0.0001), HER2 overexpression (p = 0.0085), estrogen and progesterone receptor negativity (p < 0.0001 each), and reduced survival (p = 0.03). Conclusion: Our data demonstrate that GATA3 positivity can occur in various tumor entities. Low levels of GATA3 reflect cancer progression and poor patient prognosis in breast cancer.

Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis

Introduction: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. Methods: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). Results: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III–IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. Conclusion: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.

A Rare Case of Hepatic Flexure Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC)

A Colorectal neuroendocrine carcinoma (CRNEC) is a rare malignancy of the colon. It is a tumour with a heterogeneous presentation, further complicated by its disunified nomenclature, which imposed a challenge in detection and management. We present a rare case of hepatic flexure neuroendocrine carcinoma in a 47-year-old lady who complained of 5 months history of progressively worsening, intermittent colicky central abdominal pain, altered bowel habit, vomiting, and significant weight loss. She presented with lethargy, distended abdomen and fullness at its centre. The abdominal x-ray showed generalised bowel dilatation, with the subsequent CT scan abdomen showing obstructed hepatic flexure tumour. She underwent emergency exploratory laparotomy and right hemicolectomy with a double-barrel stoma. Intraoperatively, a hepatic flexure tumour, an engorged and nodular appendix with multiple mesenteric lymph nodes. Her recovery was unremarkable. Histopathology examination showed neuroendocrine tumour Grade 3 arising from hepatic flexure with no appendiceal involvement.

Resection of primary lesion with chemotherapy improves the survival of patients with metastatic colorectal neuroendocrine carcinoma.

To evaluate the effect of resection of primary lesion and chemotherapy on survival of patients with metastatic colorectal neuroendocrine carcinoma (CRNEC). Clinical data of 393 patients with metastatic CRNECs between January 2010 and December 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, including 171 patients who received resection of primary lesion and 221 patients who did not undergo surgery. With the propensity score matching method 172 non-operated patients were selected as controls. Kaplan-Meier method and Log-rank test were used to evaluate the survival differences, while the prognostic factors were analyzed by Cox proportional-hazards model. Metastatic CRNEC patients from January 2001 to December 2021 in Affiliated Jinhua Hospital, Zhejiang University School of Medicine were selected for validation. Compared with non-operated patients, patients who received resection had longer cause-specific survival ( P<0.05). Patients with resected positive lymph nodes>8 had a poorer prognosis compared to those with resected positive lymph nodes≤8 ( P<0.05). Multivariate analysis showed that gender, location of primary lesion and treatments were independent risk factors for cause-specific survival in patients with metastatic CRNEC (all P<0.05). For metastatic CRNEC patients with resection of primary lesion, rectal neuroendocrine carcinoma, positive resected lymph nodes≤8 and resection of primary lesion combined with chemotherapy were associated with better cause-specific survival (all P<0.05). Patients with metastatic CRNEC may benefit from resection of primary lesion, and resection of primary lesion combined with chemotherapy might be the better strategy for metastatic CRNECs. The number of positive lymph nodes resected is correlated with the prognosis of patients.

Epidemiological, clinical and endoscopic characteristics of colorectal neuroendocrine neoplasms: a population-based study in the Netherlands.

Background and study aims Neuroendocrine neoplasms (NEN) account for a small number of colorectal neoplasms. Endoscopic detection is essential for diagnosis, treatment and follow-up. Little is known about incidence of NENs in colonoscopy populations or the relationship between clinical, endoscopic and histopathologic features. We evaluated epidemiology, endoscopic and clinical characteristics of colorectal NENs in a population-based cohort. Patients and methods Medical records of NEN cases were cross-linked with the national pathology database from January 2001 to December 2015, in South Limburg County, the Netherlands, covering four endoscopy units. Senior pathologists reviewed and classified NENs using World Health Organization 5th edition (2019) guidelines. Results The number of colorectal NEN diagnoses was stable over time with 0.6 NEN per 1,000 patients. A total of NENs were detected in 85 patients: 65 neuroendocrine tumors (NETs) and 20 poorly differentiated neuroendocrine carcinomas (NECs). Rectal NETs were usually small sessile/submucosal lesions with yellowish (lipoma-like) color. Colonic NETs were larger sessile/submucosal lesions with darker color compared to background. Colorectal NECs presented as large, dark-colored lesions with ulcerated/necrotizing areas. Conclusions Our population-based data point to a stable and low incidence of 0.6 NEN per 1,000 patients in the Netherlands. Rectal NETs mainly present as small sessile yellowish lesions. Colonic NETs present as larger and darker lesions than background mucosa and NECs as darker lesions than background with ulceration/necrosis. Standardized endoscopic characterization of colorectal NENs is necessary to improve recognition of these lesions and provide a basis for evidence-based treatment and surveillance recommendations.

Acquired resistance to BRAF inhibitors is mediated by BRAF splicing variants in BRAF V600E mutation-positive colorectal neuroendocrine carcinoma

Neuroendocrine carcinomas (NECs), a poorly differentiated subtype of neuroendocrine neoplasms, are aggressive and have a poor prognosis. Colorectal neuroendocrine carcinomas (CRC-NECs) are observed in about 0.6% of all patients with CRC. Interestingly, patients with CRC-NECs show higher frequencies of BRAF mutation than typical CRC. BRAF V600E mutation-positive CRC-NECs were shown to be sensitive to BRAF inhibitors and now are treated by BRAF inhibitors. Similar to the other BRAF V600E mutated cancers, resistances against BRAF inhibitors have been observed, but the resistance mechanisms are still unclear. In this study, we established BRAF V600E mutated CRC-NEC cell line directly from surgical specimens and experimentally obtained BRAF inhibitor dabrafenib resistant cell lines. The resistant cells are revealed to express at least three types of BRAF splicing variants harboring V600E-mutation, and contribute to RAF/MEK/ERK pathway activation. In these cells, MEK and ERK inhibitors but not dabrafenib significantly suppressed cell growth and survival. Thus, in BRAF V600E mutation-positive CRC-NECs, BRAF splicing variants activate the RAF/MEK/ERK pathway and contribute to acquire BRAF inhibitor resistance. Hence, MEK or ERK are potential therapeutic targets to overcome BRAF resistance.

A case of strongly suspected Lynch syndrome with colorectal neuroendocrine carcinoma

BackgroundNeuroendocrine cell carcinomas (NEC) of the colon and rectum are uncommon, representing ~ 0.1% of all colorectal carcinomas. They are associated with a much worse prognosis compared to adenocarcinoma of the colon and rectum, as death occurs in approximately half of all patients within 1 year. Lynch syndrome (LS) is the most common cause of inherited colorectal cancer, accounting for 2–4% of newly diagnosed colorectal cancer cases. This case is extremely rare which was strongly suspected LS as the background, and NEC as the histological type of colorectal cancer.Case presentationThe patient was a 44-year-old man presenting with vomiting as the main complaint. He had undergone ileocecal resection for cecal cancer at age 29. The diagnosis was obstructive descending colorectal cancer, and colonoscopy revealed tumors in the rectum and sigmoid colon in addition. Due to multiple occurrences of colorectal cancer and its prevalence in the patient’s family, LS was suspected. The operation which was a subtotal proctocolectomy was performed. Pathological analysis revealed complete curative resection and the descending colon cancer of the obstructed portion was at the most advanced pathological Stage IIIC in UICC TNM classification, and the tissue type was a NEC. The Ki-67 index was 70%. The results of the microsatellite instability (MSI) test showed high-frequency MSI. The BRAF V600E variant was negative. The immunoexpression of MLH1 was positive, MSH2 was negative, PMS2 was positive, and MSH6 was negative.ConclusionsExtended surgery is recommended for incipient colorectal cancer in LS cases in order to reliably reduce the risk of developing metachronous colorectal cancer. The survival outcome of surgery alone on digestive tract NECs, even locoregional lesions that are completely resection, is extremely poor. It is currently unclear if digestive tract NECs develop more readily in patients with LS. The accumulation of additional cases is necessary.

TGF-β1 increases cellular invasion of colorectal neuroendocrine carcinoma cell line through partial epithelial-mesenchymal transition

Epithelial–mesenchymal transition (EMT) plays a pivotal role in cancer progression and metastasis in many types of malignancies, including colorectal cancer. Although the importance of EMT is also considered in colorectal neuroendocrine carcinoma (NEC), its regulatory mechanisms have not been elucidated. We recently established a human colorectal NEC cell line, SS-2. In this study, we aimed to clarify whether these cells were sensitive to transforming growth factor beta 1 (TGF-β1) and whether EMT could be induced through TGF-β1/Smad signaling, with the corresponding NEC cell-specific changes in invasiveness. In SS-2 cells, activation of TGF-β1 signaling, as indicated by phosphorylation of Smad2/3, was dose-dependent, demonstrating that SS-2 cells were responsive to TGF-β1. Analysis of EMT markers showed that mRNA levels changed with TGF-β1 treatment and that E-cadherin, an EMT marker, was expressed in cell-cell junctions even after TGF-β1 treatment. Invasion assays showed that TGF-β1-treated SS-2 cells invaded more rapidly than non-treated cells, and these cells demonstrated increased metalloproteinase activity and cell adhesion. Among integrins involved in cell-to-matrix adhesion, α2-integrin was exclusively upregulated in TGF-β1-treated SS-2 cells, but not in other colon cancer cell lines, and adhesion and invasion were inhibited by an anti-α2-integrin blocking antibody. Our findings suggest that α2-integrin may represent a novel therapeutic target for the metastasis of colorectal NEC cells.

Colorectal neuroendocrine carcinoma with squamous cell differentiation: a rare and unusual tumour

Background: Neuroendocrine carcinoma (NEC) of the colorectum is rare, accounting for 0.4% of all colorectal neoplasms.1 Squamous cell carcinoma (SCC) of the gastrointestinal tract is also a rare entity and accounts for 0.1–0.25% per 1000 cases of colorectal carcinoma.2 World Health Organization (WHO) classification defines mixed adeno-neuro-endocrine carcinoma as a neoplasm with both exocrine and neuroendocrine components, with each component exceeding 30%. Aim: We present a rare case of a patient with colorectal neuroendocrine carcinoma with squamous differentiation. Method: An 86-year-old gentleman presented with right sided abdominal pain. A colonic mass was noted on CT scan with multiple liver lesions. Subsequent right hemicolectomy revealed an obstructive hepatic flexure tumour. Results and conclusions: Histopathological examination of the mass revealed a high grade neuroendocrine carcinoma (NEC) with diffuse sheets and cords of epithelial cells with crowded nuclei, scant cytoplasm and frequent mitotic figures (23 per 10 high-power field). Amongst the NEC component, small areas (less than 30% of the tumour volume) comprising larger epithelial cells with abundant eosinophilic cytoplasm and areas suggestive of keratinisation were noted. The NEC component was positive for synaptophysin and CD56 immunohistochemistry with a Ki67 proliferation index of 80–90% and negative for P40 and CK5/6 immunohistochemistry. In contrast, the areas with large eosinophilic cells were positive for P40 and CK5/6 immunohistochemistry, whilst negative for synaptophysin and CD56 immunohistochemistry. The tumour exhibited aggressive behaviour with lymphovascular, perineural and venous invasion and lymph node metastases. Neuroendocrine carcinomas and squamous cell carcinomas of the colorectum are rare and extremely aggressive neoplasms3 on their own merits. This phenomenon of mixed neuroendocrine carcinoma with squamous cell differentiation is an unusual and rare pathology which lacks evidence-based guidelines for therapy. It is worth documenting as the optimal therapeutic strategy remains the main challenge.

Comprehensive analysis of mutational and clinicopathologic characteristics of poorly differentiated colorectal neuroendocrine carcinomas

Poorly differentiated neuroendocrine carcinoma (NEC) is a rare subtype of colorectal cancer (CRC). This study aimed to investigate clinicopathologic characteristics of colorectal NECs and elucidate genomic differences and similarities between colorectal NECs and colorectal adenocarcinomas (ACs). A total of 30 colorectal NECs were screened for frequently identified CRC oncogenic driver genes by targeted next-generation sequencing of 382 genes. The median age of the patients was 67 years (range, 44 to 88 years). NECs occurred predominantly in the rectum (47%) and exhibited multiple adverse prognostic pathologic factors, including frequent lymphatic and vascular invasions, high rates of lymph node metastasis and distant metastasis and advanced TNM stage. The 1-, 3-, and 5-year overall survival rates of NEC patients were 46.7%, 36.4%, and 32.7%, respectively, with a median overall survival period of 11.5 months. In a molecular analysis, NECs showed high rates of BRAF mutation (23%), predominantly p.V600E (71%), and alterations in RB1 (47%), particularly deletion (57%). The frequencies and distributions of other genes, such as KRAS, APC, SMAD4, and PIK3CA, and microsatellite instability status were similar to those of ACs. These findings provide beneficial information for selecting therapeutic options, including targeted therapy, and a better understanding of the histogenesis of this tumour.

Poorer prognosis for neuroendocrine carcinoma than signet ring cell cancer of the colon and rectum (CRC-NEC): a propensity score matching analysis of patients from the Surveillance, Epidemiology, and End Results (SEER) database.

Colorectal neuroendocrine carcinomas (CRC-NECs) are rare, comprising < 1% of colorectal cancers. This study aimed to assess the incidence, clinicopathologic characteristics, prognostic factors, and treatment outcomes of CRC-NEC. We analysed the Surveillance, Epidemiology, and End Results (SEER) database to identify patients from 20 to 74years old diagnosed with CRC-NEC or common CRC (non-NEC) during 2004-2013. Log-rank testing was conducted to assess survival differences. A competing-risks regression model was used to adjust for covariate effects in the propensity score-matched (PSM) cohort, and adjusted hazard ratios (HRs) were calculated for the raw and PSM cohorts. We identified 67,484 patients (344 CRC-NEC and 67,140 non-NEC). Lymph node metastasis (LNM) was more common in CRC-NEC (75.29%, n = 259) than in non-NEC (51.53%, n = 34,600) (P < 0.001); 56.40% (n = 194) of CRC-NECs were located on the right side, while 18.31% (n = 63) were located on the left side, with a statistically significant difference in distribution (P < 0.001) compared to that in non-NEC CRC. Multivariate analysis indicated that a left-side location was an independent adverse prognostic factor for CRC-NEC (P = 0.043). CRC-NEC had the poorest cancer-specific survival (median CSS, 9.0months) among assessed cancers, even poorer than that of signet ring cell cancer (median CSS, 24.0months). However, both radical operation (P = 0.007) and chemotherapy (P = 0.008) were beneficial for CSS. NEC is a rare and extremely aggressive tumour with a poor prognosis. Right-side NEC has a better prognosis than left-side NEC. Early diagnosis, radical surgery, and chemotherapy are imperative for improving survival.

A case of colorectal large cell neuroendocrine carcinoma accompanied by disseminated peritoneal leiomyomatosis

BackgroundNeuroendocrine carcinomas (NECs) of the colon are among the rarest types of colorectal cancers. Among these, large cell type neuroendocrine carcinoma (LCNEC) is particularly rare. Colorectal NEC is an aggressive disease, and there are few reports of long-term survivors. Here, we report a case of LCNEC accompanied by disseminated peritoneal leiomyomatosis that was difficult to diagnose.Case presentationThe case involves a 62-year-old female found to be positive for fecal occult blood by medical examination. An endoscopy revealed a tumor in the ascending colon, and the biopsy revealed poorly differentiated cancer. Abnormal FDG accumulation with peritoneal thickening was visible on 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) and suspected to be peritoneal dissemination. Laparoscopic ileocecal resection was performed for the tumor of the ascending colon with abdominal wall invasion. At that time, numerous intra-abdominal nodules were observed, indicating peritoneal dissemination. The pathological diagnosis of the primary lesion was LCNEC, and the patient requested to undergo total peritoneal resection. After one course of chemotherapy with irinotecan plus cisplatin, she underwent total peritoneal resection, uterine annex resection, left inguinal lymph node resection, and intra-abdominal hyperthermic intraperitoneal chemotherapy with mitomycin C. Because a postoperative pathological examination revealed that the intra-abdominal nodules were leiomyomas, we diagnosed the patient with disseminated peritoneal leiomyomatosis. The left inguinal lymph node was diagnosed with a metastatic tumor. In summary, the final diagnosis was LCNEC in the ascending colon with inguinal lymph node metastasis. Postoperative chemotherapy has been administered to date. She is currently 18 months post-primary surgery and 15 months post-peritonectomy without apparent recurrence or metastatic findings.ConclusionWe experienced a case of Stage IVa colorectal LCNEC accompanied by disseminated peritoneal leiomyomatosis. Although the prognosis is generally poor, multidisciplinary treatment for advanced colorectal LCNEC may result in a favorable outcome for some patients. If peritoneal dissemination is suspected during operation, sampling of the nodule to confirm the pathological diagnosis is advisable.

Genetic Characteristics of Colorectal Neuroendocrine Carcinoma: More Similar to Colorectal Adenocarcinoma

BackgroundDespite the increasing incidence rate of colorectal neuroendocrine carcinoma (CR-NEC), there are still few sequencing data to depict the genomic characteristics of CR-NEC. Patients and MethodsNext-generation sequencing data of CR-NEC, colorectal adenocarcinoma (COREAD), lung neuroendocrine carcinoma (lung NEC), and gastrointestinal neuroendocrine tumor (GI-NET) were retrieved from the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) database platform. Overall survival data of patients were obtained from cBioPortal. ResultsThe median tumor mutation burden (TMB) was 5.18 per megabase. TP53 (65.5%), APC (59.5%), KRAS (36.9%), BRAF (20.2%), and RB1 (16.7%) were the most common genes harboring somatic mutations. Nearly all of the BRAF mutations (88.2%) caused V600E. The most common copy number alterations were gain of MYC (12.3%), loss of RB1 (10.7%), and loss of PTEN (5.4%). Compared to lung NEC and GI-NET, the genetic characteristics of CR-NEC were more similar to that of COREAD. CR-NEC had a higher rate of potentially targetable gene alterations compared to lung NEC and GI-NET, and BRAFV600E might be a promising treatment target. Survival analysis indicated that patients with high TMB had significantly worse survival than patients with low TMB (P < .001). In addition, KRAS and RB1 alteration were found to be correlated with worse survival (both P = .023). ConclusionCR-NEC has genetic alterations that are more similar to COREAD than other entities. A substantial group of CR-NEC harboring potentially targetable alterations (BRAFV600E) deserves to be tested in clinical practice.

Should immunohistochemical expression of mismatch repair (MMR) proteins and microsatellite instability (MSI) analysis be routinely performed for poorly differentiated colorectal neuroendocrine carcinomas?

SummaryColorectal poorly differentiated neuroendocrine carcinomas (NECs) are typically associated with poor outcomes. The mechanisms of their aggressiveness are still being investigated. Microsatellite instability (MSI) has recently been found in colorectal NECs showing aberrant methylation of the MLH1 gene and is associated with improved prognosis. We present a 76-year-old lady with an ascending colon tumour showing features of a pT3 N0 R0, large cell NEC (LCNEC) following right hemicolectomy. The adjacent mucosa showed a sessile serrated lesion (SSL) with low-grade dysplasia. Immunohistochemistry showed loss of expression for MLH1 and PMS2 in both the LCNEC and dysplastic SSL. Molecular analysis indicated the sporadic nature of the MLH1 mismatch repair (MMR) protein-deficient status. Our patient did not receive adjuvant therapy and she is alive and disease-free after 34 months follow-up. This finding, similar to early-stage MMR-deficient colorectal adenocarcinoma, is likely practice-changing and will be critical in guiding the appropriate treatment pathway for these patients. We propose that testing of MMR status become routine for early-stage colorectal NECs.Learning points:Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are known to be aggressive and typically associated with poor outcomes.A subset of colorectal NECs can display microsatellite instability (MSI) with mismatch repair (MMR) protein-deficient status.MMR-deficient colorectal NECs have been found to have a better prognosis compared with MMR-proficient NECs.MMR status can be detected using immunohistochemistry.Immunohistochemistry for MMR status is routinely performed for colorectal adenocarcinomas.Immunohistochemical expression of MMR protein and MSI analysis should be performed routinely for early-stage colorectal NECs in order to identify a subgroup of MMR-deficient NECs which are associated with a significantly more favourable prognosis.

Homogeneous MMR Deficiency Throughout the Entire Tumor Mass Occurs in a Subset of Colorectal Neuroendocrine Carcinomas

Neuroendocrine neoplasms comprise a heterogeneous group of tumors, categorized into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) depending on tumor differentiation. NECs and high-grade NETs (G3) confer a poor prognosis, demanding novel treatment strategies such as immune checkpoint inhibition in tumors with microsatellite instability (MSI). To study any possible intratumoral heterogeneity of MSI, a tissue microarray (TMA) containing 199 NETs and 40 NECs was constructed to screen for MSI using immunohistochemistry (IHC) for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. Four cases suspicious for MSI were identified. Validation of MSI by repeated IHC on large sections and polymerase chain reaction (PCR)–based analysis using the “Bethesda Panel” confirmed MSI in 3 cecal NECs. One pancreatic NET G3 with MSI-compatible TMA results was MMR intact on large section IHC and microsatellite stable (MSS). The remaining 235 tumors exhibited intact MMR. Protein loss of MLH1/PMS2 was found in two and MSH6 loss in one cancer with MSI. Large section IHC on all available tumor-containing tissue blocks in NECs with MSI did not identify aberrant tumor areas with intact MMR. Our data indicate that MSI is common in colorectal NECs (3 out of 10) but highly infrequent in neuroendocrine neoplasms from many other sites. The lack of intratumoral heterogeneity of MMR deficiency suggests early development of MSI during tumorigenesis in a subset of colorectal NECs and indicates that microsatellite status obtained from small biopsies may be representative for the entire cancer mass.

Complete Response and Immune-Mediated Adverse Effects With Checkpoint Blockade: Treatment of Mismatch Repair-Deficient Colorectal Neuroendocrine Carcinoma.

Complete Response and Immune-Mediated Adverse Effects With Checkpoint Blockade: Treatment of Mismatch Repair-Deficient Colorectal Neuroendocrine Carcinoma.