Signet Ring Cell Differentiation Research Articles

Advanced signet ring cell type gastroesophageal cancers in Latin American patients age 40 and below: A summary of one tertiary care center's experience and a review of the literature.

e16069 Background: Gastric Cancer mortality rates in Latin American countries of Central and South America (LA) are among the highest in the world. After observing multiple cases of advanced gastric adenocarcinoma (GA) with signet ring cell differentiation in young immigrants from LA, we sought to understand the prevalence and demographics of young-onset gastric cancer at our institution. Methods: We used the Inova Fairfax Hospital cancer registry to perform a retrospective cohort study by identifying all patients ≤ 40 from 2013-2022 with 1) GA, and 2) all cancers, and comparing the percentage of LA patients in each group. We noted a trend towards high rates of GC in young immigrants of LA six years ago, and now provide an updated analysis. We then reviewed phenotypic characteristics of each tumor, including signet ring cell differentiation, Her-2/Neu overexpression, and H. Pylori status and the time interval between diagnosis and death. Results: From 2013-2022, 21/37 patients (56.8%) ≤ 40 with GA were from LA (Table 1), with the majority from El Salvador. 95% (20/21) of LA patients had tumors with signet ring cell morphology, 88% (14/16) of non-LA patients had tumors with signet ring cell morphology. In comparison, patients that self-identified as “Hispanic/Spanish” made up 8.1% of subjects ≤ 40 with all cancers during the same time period. Conclusions: At our tertiary care center, Stage IV signet ring cell gastric cancer is highly prevalent in young patients from Latin America. Further exploration of epidemiological risk factors is warranted. [Table: see text]

18F-fluorodeoxyglucose positron emission tomography/computed tomography findings of breast cancer with signet ring cell differentiation: A single-center experience

Aim: Due to the low incidence of breast cancer with signet ring cell (SRC) differentiation, which constitutes less than 1% of all breast cancers, little is known about its imaging features. The aim of this study was to evaluate the utility of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in staging breast cancer with SRC differentiation.
 
 Methods: We conducted a retrospective analysis of 14 patients with histologically confirmed breast cancer with SRC differentiation who underwent 18F-FDG PET/CT at our institution between 2014 and 2023. The imaging findings were analyzed in terms of maximum standardized uptake value (SUVmax), lesion size, and the presence of regional or distant metastases were statistically evaluated.
 
 Results: The histological subtypes of SRC differentiated primary tumors were 9 invasive lobular, and 5 invasive ductal carcinoma. More intense 18F-FDG uptake was observed in primary tumoral lesions of the ductal subtype (mean SUVmax: 18.8±9.8; range: 2.6–28.9) compared to the lobular subtype (mean SUVmax: 2.6±1.3; range: 1.5–5.1) (p=0.007, Z=2.600). Among the patients included in the study, axillary lymph node metastasis was present in 64% (n=9) of the cases, with lymph node metastasis identified in five cases classified as ductal carcinoma. Additionally, distant organ metastasis was identified in 21% (n=3) of patients, comprising two patients with ductal carcinoma and one with lobular carcinoma.
 
 Conclusion: Despite the general consensus that signet-ring cell tumors have a low affinity for 18F-FDG, our study has observed the possibility of high 18F-FDG uptake in cases of ductal carcinoma. However, in cases of lobular carcinoma, where 18F-FDG uptake tends to be low, considering alternative PET radiopharmaceuticals for imaging could be a viable option.

Early onset, development and histological features of gastric signet-ring cell carcinoma.

To explore the early onset, development and histological features of gastric signet-ring cell carcinoma (SRCC). Three hundred and sixty-two patients with differentiated adenocarcinoma with signet-ring cells were enrolled. Histomorphological and immunohistochemical features and patterns of the specimens were observed in detail. Infection of the gastric mucosa, especially by Helicobacter pylori, can cause massive cell proliferation and transformation in the deep gastric foveola, the isthmus of the gastric gland, and the proliferative zone of the upper neck of the gland. Signet-ring-like heterocysts monoclonally proliferated after the redifferentiation and reproliferation, extending horizontally along the gastric foveola. Gastric foveolar-type SRCC grew infiltratively into the lamina propria of the mucosa and the submucosa, signet-ring cells could differentiate into undifferentiated adenocarcinoma with signet-ring cell differentiation, mucinous adenocarcinoma with signet-ring cell differentiation, gastric adenocarcinoma with signet-ring cell differentiation, and fundus gland adenocarcinoma with signet-ring cell differentiation. Early SRCC developed from the proliferative zones of the fundus of the gastric foveola and the neck of the gastric gland, growing horizontally along the gastric foveola. It developed into gastric adenocarcinoma with signet-ring cell differentiation after reproliferation and retransformation in the mucosa.

The clinicopathological and immunohistochemical features of breast carcinomas with signet-ring-cell differentiation

BackgroundThis study investigated the clinicopathological features, immunophenotypic characteristics and differential diagnosis of primary breast carcinomas with signet ring cell differentiation, as well as differences in the traits of signet ring-like cell mucin.MethodsA total of five cases of primary breast cancer diagnosed with signet ring cell differentiation and treated at The First People’s Hospital of Jingmen from January 2016 to December 2021 were collected. HE, immunohistochemical staining, and AB-PAS staining were used for the analysis.ResultsAlthough we strictly selected all the primary breast cancer cases with signet ring cell differentiation, there were differences in the arrangement of the cells and the grading of nuclei. Our immunohistochemical results showed that the ER was consistently strongly positive, and the PR expression was not consistent, while all the cases of HER2 were negative. CK7 was negative in one case, and CK20 and CK5/6 were not expressed in all the cases. The mucin MUC1 was positive and showed two patterns. MUC2 was strongly positive in all the cases. All the cases were negative for CDX2, SATB2, PAX8, TTF-1, and Napsin A, while the positive expression of COX2, Villin, and WT-1 was not constant. One case expressed neuroendocrine markers. The expression level of Ki67 was between 10 and 30%. AB (pH 2.5)-PAS staining revealed that the intracellular mucus contained more cells with neutral mucus, while the extracellular mucus was mainly acidic.ConclusionWe found that histological morphology, cell morphology, and nuclear grading differentiate among different cases. The immunohistochemical characteristics of primary breast cancers diagnosed with signet ring cell differentiation are helpful for identification. The differences in the expression patterns of mucins may be related to unfavorable clinicopathological factors, but their usefulness as a prognostic marker remains to be further understood. The heterogeneity of cell mucus, the differentiation of tumor cells, and the phenotypic changes of tumors also need further study.

S3558 A Tale of Two Sisters: Two Pediatric Cases Within a Familial Cluster of Hereditary Diffuse Gastric Carcinoma

Introduction: We report a case of HDGC in two sisters, (10 and 15 years old) and their father (41 years old). Case Description/Methods: Our patient is a 15-year-old Caucasian female who initially presented to our clinic with a 4-month history of right lower quadrant tenderness and generalized abdominal pain, which she characterized as “stabbing pain.” Review of systems was significant for intermittent diarrhea and constipation. Family history was significant for a paternal great-aunt who reportedly died from gastric cancer at age 28. Abdominal ultrasound showed no significant abdominal pathology and no appreciable stomach wall thickening. EGD revealed diffuse mild inflammation of the stomach with normal appearing rugae without ulceration or masses and normal proximal duodenum. Biopsy results from the antrum revealed poorly differentiated signet ring cell carcinoma. The patient underwent a second EGD and imaging to confirm and stage the cancer. The patient subsequently underwent a laparoscopic roux-en-Y esophagojejunostomy, jejunojejunostomy with exploratory laparoscopy. Based upon the unusual occurrence of SRCC in a young female, the patient and her family underwent genetic testing. The patient was found to be positive for a CDH1/E-cadherin mutation. It was found that the patient’s father and her 10-year-old sister also carried this mutation. The 10-year-old sister and the father underwent screening EGD with greater than 40 biopsies taken throughout the stomach, esophagus, and duodenum in representative areas. Surprisingly, both patients were found also to have gastric SRCC. The father has since undergone chemotherapy, radiation, and a laparoscopic roux-en-Y esophagojejunostomy, jejunojejunostomy. The family is opting for conservative management at this time for the 10-year-old patient with plans to undergo the same surgery when she is older (Figure). Discussion: Gastric carcinoma in the pediatric population is exceedingly rare. HDGC should be considered when a patient presents with gastrointestinal symptoms and has a positive family history of gastric cancer among 1st and 2nd degree relatives, particularly if a relative was diagnosed before the age of 50. For carriers of the CDH1 mutation, prophylactic total gastrectomy is recommended with intraoperative confirmation of squamous epithelium in the esophagus at the proximal margin and duodenal mucosa at the distal margin. If gastrectomy is contraindicated, yearly endoscopic surveillance with random biopsies is recommended.Figure 1.: Biopsy from gastric antrum demonstrating poorly differentiated signet ring cell carcinoma present in the lamina propria.

The relationship of tumor budding with GOLPH3 expression and histopathological prognostic parameters in colorectal adenocarcinoma

ObjectiveTumor budding is an independent poor prognostic parameter in colorectal carcinoma (CRC). Golgi phosphoprotein 3 (GOLPH3) has been investigated in many solid organ tumors and has been associated with poor prognosis. In this study, the relationship of tumor budding and GOLPH3 and histopathological prognostic markers was investigated. Materials and methods140 colon resection materials diagnosed with adenocarcinoma between 2011 and 2018 were included in this study. Cases were reanalysed for their age, gender, tumor localization and size, histological grade, mucinous and signet ring cell differentiation, depth of invasion, lymphovascular and perineural invasion, stromal and intraepithelial tumor infiltrating lymphocyte (TIL), Crohn-like lymphoid reaction, peritumoral lymphocytic response, overall lympocytic score and lymph node metastasis. GOLPH3 antibody was applied to the sections containing the most dense tumor budding. The relationship between tumor budding and GOLPH3 expression, histopathological parameters and overall survival time was evaluated. ResultsTumor budding was detected in 72 (51.4%) of 140 tumors. There was correlation between tumor budding and localization, size, histological type and grade, lymphovascular and perineural invasion, there was no relation with GOLPH3 expression. GOLPH3 expression was positive in 106 (75.7%) of tumors. Significant correlations were found between GOLPH3 expression and signet ring cell differentiation, stromal TIL, peritumoral lymphocytic response and overall lymphocytic score. ConclusionTumor budding and GOLPH3 expression are not correlated in CRC, but both are correlated to important prognostic histopathological parameters. In addition, tumor budding and GOLPH3 expression were not effective in overall survival, however, both parameters should be evaluated in a larger series.

Synchronous \u201cskip\u201d facial metastases from colorectal adenocarcinoma: a case report and review of literature

BackgroundSkin metastases from colorectal adenocarcinoma are rare conditions that are metachronous in most of cases and may represent the first sign of a recurrence. These lesions are usually located to the abdominal wall on postoperative scars, perineum and chest due to direct spread from the tumor or to the lymphatic and venous dissemination. We describe a rare case of synchronous skin metastases in a patient affected by sigmoid adenocarcinoma with no sign of liver and lung repetitive lesions.Case presentationWe admitted a 59 years old male, with no relevant medical history. He was evaluated by our tertiary center of colorectal surgery complaining diarrhoea and abdominal pain. The physical examination revealed a palpable mass in left flank of the abdomen. The colonoscopy showed a sub-stenosis of the sigmoid colon (G2 adenocarcinoma). No repetitive lesions were detected by the preoperative CT scan. The patient reported a rapid grow of a soft supralabial and chin nodules in the last 2 months, which he believed to be related to the use of the mask due to COVID-19 pandemic. A laparoscopic left hemicolectomy with complete mesocolic excision and a local excision of both facial nodules were performed. The histological examination revealed a poorly differentiated signet ring cell colorectal adenocarcinoma with metastases in seven pericolic lymphonodes. The excisional biopsy of the skin nodules revealed a subcutaneous metastases from primary colorectal tumour.ConclusionsAs far as we know, synchronous facial metastases from colorectal cancer in the absence of any other metastases has never been described before. The onset of new skin nodules in patients affected by colorectal cancer should raise-up the clinical suspicion of metastatic lesions even when repetitive lesions are not detected in the liver or lungs.

Association of clinicopathological features with DNA mismatch repair status among colorectal cancer patients presenting to a Tertiary Care Cancer Hospital

Background: About 12%–15% of sporadic colorectal cancers (CRCs) display a defect in the DNA mismatch repair (MMR) system resulting in microsatellite instability (MSI). Many authors have described certain clinicopathological predictors of MSI and confirmed with ancillary studies. The purpose of this study was to determine the clinicopathological features and their association with MMR deficiency (dMMR) among CRC patients. Materials and Methods: A cross-sectional study was designed among patients presented with CRC. A predesigned proforma was used to document the particulars of the patient along with histological parameters to be assessed. Cases were analyzed for dMMR using MLH1 and MSH2 immunostains and categorized into dMMR and MMR-proficient. The association of clinicopathological features with MMR status was statistically analyzed. Results: Sixty-four CRC cases were analyzed in the study. Thirteen out of 64 cases showed dMMR. Most of the dMMR tumors were located in the right-sided colon (P < 0.001). Three patients with a family history of CRC exclusively had dMMR (P = 0.01). Mucinous (P = 0.04), signet ring cell differentiation (P = 0.04), and lack of dirty necrosis (P < 0.001) showed a significant difference between deficient and proficient MMR categories. Gender, mean tumor-infiltrating lymphocytes per hpf, Crohn's-like reaction, and tumor stage did not show any significant difference between the two categories. Conclusions: Clinicopathological features such as family history, tumor location, tumor size, histologic type, tumor differentiation, mucinous, signet ring cell component, and dirty necrosis are associated with MMR status in CRC.

Contemporary outcome of liver transplantation for bilobar multiple colorectal liver metastasis

During the last decade, increasing evidence suggest that highly selected patients with colorectal liver metastases (CRLM) can obtains superior survival by liver transplantation. Three scoring systems may be utilized to predict post-transplant survival in CRLM. Pre transplant factors associated with unfavorable outcome are maximal tumor diameter > 55 mm, CEA > 80 micrograms/mL, unresponsiveness to chemotherapy and a time interval from diagnosis to transplant less than 24 months. These 4 factors are assessed in the Oslo Score, and scores from 0-2 yield a 5-year overall survival of about 67%-70%. Further refined selection include the metabolic tumor volume (MTV) at PET CT. This is defined as an uptake of 40% of standardized maximal uptake (SUVmax). Calculated per patient as the sum of MTV in all lesions, a MTV value < 70 cc is associated with post-transplant survival of 78%. The Fong Clinical Risk Score (FCRS) offers an even more stringent selection of candidates and scores of 0-2 have in the published literature demonstrated 100% 5-year overall survival. Caution against transplantation is advised in patients with right sided primary tumors, undifferentiated og signet ring cell differentiation, N" status of the primary og BRAF mutation. The outcomes referenced are probably not limited only to non-resectable CRLM. It is therefore possible that some few patients currently offered liver resection could have a clinically significant treatment benefit by liver transplantation, but future studies are needed to clarify this question. Since CRLM patients, by definition have metastatic disease, recurrence remains a problem. Thus, assessing the balance between survival and recurrence after transplantation remains a difficult dilemma. About two thirds of the recurrences are slow growing lung metastases. The experience to date indicates that pulmonary recurrence alone has a modest impact on survival outcomes, since many of them can be resected with curative intent. Further studies focusing on this group of patients will be important for the development of this field of transplant oncology. Liver transplantation for secondary liver tumors should be implemented in accordance with stringent transplant criteria and preferably in the context of prospective trials. Expansion of the donor pool by utilizing extended criteria donors, partial liver transplantation and possibly living donor liver transplantation could be considered for this indication.

Pathohistological and Immunohistochemical Analysis of Primary Invasive Ductal Breast Carcinoma with Signet-Ring Cell Differentiation- Differential Diagnosis, Prognosis and Complex Treatment

Primary signet ring cell carcinoma (PSRCC) of the breast is a rarely diagnosed neoplasm. We present a 76-year-old woman with a tumor formation in the left mammary gland, who has been self-medicating for a year. Pathohistological and immunohistochemical analysis proved rare primary invasive ductal carcinoma with focal (over 90%) signet ring cell differentiation, size 4 cm / 3.5 cm / 2 cm, moderately differentiated (G2). Complex oncological treatment, including radical mastectomy with axillary dissection, 6 courses of systemic adjuvant chemotherapy, radiotherapy of the chest wall and regional lymph nodes with TD 46 Gy and antiestrogenic hormone therapy, was performed. The diagnosis and the differential diagnosis of this rare tumor require precise pathohistological and immunohistochemical analysis. The prognosis and complex treatment depend on the clinical stage, hormonal and HER2 status. In locally advanced PSRCC of the breast with moderately differentiation, the combination of surgery, systemic chemotherapy, postoperative radiotherapy and antiestrogenic hormone therapy achieves long-term local tumor control without distant metastases for nearly two years.

Impact of pathological tumor response after CROSS neoadjuvant chemoradiotherapy followed by surgery on long-term outcome of esophageal cancer: a population-based study

Background With increasing interest in organ-preserving strategies for potentially curable esophageal cancer, real-world data is needed to understand the impact of pathological tumor response after neoadjuvant chemoradiotherapy (CRT) on patient outcome. The objective of this study is to assess the association between pathological tumor response following CROSS neoadjuvant CRT and long-term overall survival (OS) in a nationwide cohort. Material and methods All patients diagnosed in the Netherlands with potentially curable esophageal cancer between 2009 and 2017, and treated with neoadjuvant CRT followed by esophagectomy were included. Through record linkage with the nationwide Dutch Pathology Registry (PALGA), pathological data were obtained. The primary outcome was pathological tumor response based on ypTNM, classified into pathological complete response (ypT0N0) and incomplete responders (ypT0N+, ypT+N0, and ypT+N+). Multivariable logistic and Cox regression models were used to identify predictors of pathological complete response (pCR) and survival. Results A total of 4946 patients were included. Overall, 24% achieved pCR, with 19% in adenocarcinoma and 42% in squamous cell carcinoma. Patients with pCR had a better estimated 5-year OS compared to incomplete responders (62% vs. 38%, p< .001). Of the patients with incomplete response, ypT+N+ patients (32% of total population) had the lowest estimated 5-year OS rate, followed by ypT0N+ and ypT+ N0 (22%, 47%, and 49%, respectively, p< .001). Adenocarcinoma, well to moderate differentiation, cT3-4, cN+, signet ring cell differentiation and lymph node yield (≥15) were associated with lower likelihood of pCR. Conclusion In this population-based study, pathological tumor response based on the ypTNM-stage was associated with different prognostic subgroups. A quarter of patients achieved ypT0N0 with favorable long-term survival, while one-third had an ypT+N+ response with very poor survival. The association between pathological tumor response and long-term survival could help in more accurate assessments of individual prognosis and treatment decisions.

Congenital goiter with areas of signet ring cell differentiation in a juvenile giraffe: a very rare entity

BackgroundCongenital goiter is a common thyroid metabolic disorder characterized by low levels of thyroid hormone, subsequent secretion of excess thyroid-stimulating hormone (TSH) from the pituitary gland, and compensatory hyperplasia of the glands. The presence of signet ring cells (SRCs) does not provide sufficient evidence for the diagnosis of a thyroid tumor, making histopathological diagnosis challenging. In addition, SRCs can also appear in congenital goiter. Therefore, a comprehensive diagnosis of congenital goiter is warranted based on clinical symptoms, autopsy, histopathology, and laboratory examination.Case presentationA juvenile giraffe at the Ordos Zoo in Ordos presented with symptoms of loss of appetite, serious salivation, and slow growth rate since birth. Its height and weight were significantly lower than those of other giraffes of the same age. The animal ultimately died at 17 months of age. Autopsy revelaed that the thyroids were hard, with an uneven surface and with the presence of many small raised follicles, and dense in cross-section. Other organs were visibly atrophic. Histopathologically, diffuse follicles were irregular in size and shape in the hyperplastic goiter. Some follicles were collapsed due to lack of colloids. The follicles were lined by single or multiple layers of hyperplastic follicular cells (HFCs), some of which were exfoliated in the lumen. The HFCs were either cuboidal with eosinophilic cytoplasm and many red small granules or showed SRC differentiation, with nuclei pressed to one edge of the cell and distorted by cytoplasmic mucin that appeared as a single clear vacuole HFCs and as a foamy, multivesicular cytoplasmic material in others. Scattered necrosis of myocardial cells and hepatocytes, cerebral hemorrhage, necrosis of intestinal villi, and obvious atrophy of organs were also observed. Immunohistochemical tests were strongly positive for thyroglobulin and thyroid transcription factor-1 (TTF-1) in the cytoplasm of HFCs.ConclusionsHere we present a case of congenital goiter with areas of SRC differentiation in the thyroid of a juvenile giraffe.

S2832 Mucinous Signet-Cell Adenocarcinoma of the Ileum: A Diagnostic Challenge

INTRODUCTION: Malignancies of the small intestine are rare, and signet-ring cell carcinoma is one of the rarest forms of adenocarcinoma that can arise in the small bowel. We present a rare case of a patient who originally presented with abdominal pain and radiographic findings suggestive of ileal congestion and question of an infective process concerning for Crohn’s disease (CD). After an extensive work-up including multiple colonoscopies and computerized tomography scans (CT), the patient underwent an exploratory laparotomy and resection of an ileocolic mass was positive for signet ring cell adenocarcinoma. CASE DESCRIPTION/METHODS: A 68-year-old woman with a new diagnosis of Crohn’s disease presented as a transfer for recurrent severe lower-abdominal pain and weight loss. The patient had initially presented to an outside hospital. Family history was positive for CD. The initial CT scan revealed wall thickening and fat stranding of the terminal ileum with right lower quadrant mesenteric lymph nodes. An initial colonoscopy showed a normal colon with superficial, linear erosions in the distal rectum. The patient’s bloodwork was pertinent for an elevated C-reactive protein and calprotectin. Given these findings, the patient was diagnosed with CD and treated. After multiple readmissions for similar pain and a repeat CT scan showing a possible abscess or phlegmon, the patient was transferred. Upon arrival, the patient was hemodynamically stable with unchanged labs. A repeat colonoscopy was performed and a biopsy of the terminal ileum showed mild inflammatory changes and congestion. The pathological analysis confirmed the presence of SRCC. The patient underwent an esophagogastroduodenoscopy (EGD) to assess for malignancy, which was negative. An exploratory laparotomy was performed along with the resection of an ileocolic mass. Pathology confirmed mucinous adenocarcinoma with signet-ring cell differentiation. The patient was started on FOLFOX regimen. She is currently on her third cycle of chemotherapy and doing well with an aim to cure. DISCUSSION: The aforementioned case illuminated the diagnostic challenge of signet-cell adenocarcinoma of the ileum. This case report is important because it highlights the importance of considering malignancy in the differential diagnosis when newly diagnosed inflammatory bowel disease does not respond to treatment. Despite its rarity, clinicians should maintain a suspicion of SRCC in the absence of histological confirmation.Figure 1.: Tubulovillous adenoma. Cecal polyp showing finger-like projections formed by fibrovascular cores and lined by dysplastic epithelium. Invasive carcinoma is noted identified (H&E stain, 20x).Figure 2.: Invasive signet ring cell carcinoma of the colon with extracellular mucin pools. The tumor is seen invading the muscularis propria (arrow). A ruptured abscess is noted within the muscularis next to the invasive carcinoma (arrowhead) (H&E stain, 20x).Figure 3.: Invasive carcinoma showing signet ring cell morphology, at higher magnifications (H&E stain, Figure D: 400x).

Rectal adenocarcinoma following imperforate anus: A rare case report

Background: Anorectal malformations are a rare presentation. The standard treatment modality for imperforate anus is surgery. The abdominoperineal pull-through procedure was popular in the past for this malformation, but, with recent advancement, the posterior sagittal anorectoplasty and colostomy as a staged procedure are other options. Chronic constipation following pull-through procedures for imperforate anus may also lead to degeneration of the anorectal segment. Case Presentation: A 28-year-old male presented with the complaint of on and off constipation and painful defecation since childhood. The patient had a history of imperforate anus congenitally, for which a pull-through procedure was done after birth at another hospital. He underwent multiple surgeries for constipation. During this time period, the patient had constant complaints of difficulty in defecation and constipation, for which he used to use Hager’s dilators to dilate the anal canal. He also used per rectal enema and suppositories. His digital rectal examination showed narrowed anal opening. Colonoscopy was planned, which showed ulcerated and necrotic area at 6–8 cm from anal verge. Biopsy came out to be moderate-to-poor differentiated adenocarcinoma with signet ring cell differentiation. His computed tomography scan was performed, which showed circumferential mural thickening starting from the anal verge to the rectosigmoid junction with local infiltration to prostate, bilateral levator ani, and posterior sacral space. The patient was given a diversion colostomy and was referred for neoadjuvant chemoradiotherapy. Conclusion: All patients undergoing pull-through procedures should be closely followed in a multidisciplinary unit with interval colonoscopy for the early detection and prompt management of rectal cancer.

Intraperitoneal mitomycin C improves survival compared to cytoreductive surgery alone in an experimental model of high-grade pseudomyxoma peritonei

Pseudomyxoma peritonei (PMP) is a rare cancer commonly originating from appendiceal neoplasms that presents with mucinous tumor spread in the peritoneal cavity. Patients with PMP are treated with curative intent by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The value of adding HIPEC to CRS has not been proven in randomized trials, and the objective of this study was to investigate the efficacy of intraperitoneal mitomycin C (MMC) and regional hyperthermia as components of this complex treatment. Xenograft tissue established from a patient with histologically high-grade PMP with signet ring cell differentiation was implanted intraperitoneally in 65 athymic nude male rats and the animals were stratified into three treatment groups; the cytoreductive surgery group (CRSG, CRS only), the normothermic group (NG, CRS and intraperitoneal chemotherapy perfusion (IPEC) with MMC at 35 ºC), and the hyperthermic group (HG, CRS and IPEC at 41 ºC). The main endpoints were survival and tumor weight at autopsy. Adequate imitation of the clinical setting and treatment approach was achieved. The median survival was 31 days in the CRSG, 60 days in NG and 67 days in HG. The median tumor weights at autopsy were 34 g in CRSG, 23 g NG and 20 g in HG. In conclusion, the addition of IPEC with MMC after CRS doubled the survival time and reduced tumor growth compared to CRS alone. Adding regional hyperthermia resulted in a modest improvement of treatment outcome.

SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer

DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (p < 0.001) and in 36% of BRAF V600E mutated compared with only 13% of BRAF wild-type tumors (p < 0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with p < 0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (p < 0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (n = 131), only tumor stage (p = 0.01) and SATB2-negative and/or CDX2-negative expression (p = 0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient, BRAF-mutated, or KRAS-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer.

The Impact of Signet Ring Cell Differentiation on Outcome in Patients with Esophageal and Gastroesophageal Junction Adenocarcinoma

BackgroundLittle is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC.MethodsPatients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group.ResultsOverall, 129 (19%) of 689 patients included had SRCs (nCT: n = 64; nCRT: n = 65). The SRC group had a more advanced ypT stage (p = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range [IQR]) 2 [0–5] vs. 1 [0–3]; p = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median [IQR] 12 [5–50] vs. 23 [8–164]; p = 0.013), but not OS, compared with the non-SRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT.ConclusionsSRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS.

Metastatic Gastric Cancer Presenting as Periorbital Edema

A 53 year old male presented with recent labs and imaging concerning for periorbital cellulitis. The patient was initially admitted by ophthalmology and managed with antibiotics. He displayed minimal improvement with antibiotics, leading to the addition of systemic steroids. His condition deteriorated the following day when he developed hematemesis. Antibiotics were therefore escalated with the addition of IV Pantoprazole, and steroids were discontinued. EGD showed a large, non-bleeding ulcer with a visible vessel in the gastric body. Small, clean-based ulcers were also seen in the body and antrum. Diffuse, friable mucosa was noted throughout the stomach and biopsies were taken due to concern for malignancy. Right orbital biopsy and CT chest/abdomen/pelvis was also ordered to further evaluate for malignancy. CT showed bilateral pulmonary emboli, retroperitoneal soft tissue infiltrates, and bladder and colonic wall thickening. The patient's hematemesis recurred, necessitating repeat EGD with epinephrine injections and bipolar cautery in order to achieve hemostasis. Gastric biopsies revealed invasive and poorly differentiated Signet Ring Cell Carcinoma (SRCC) with a background of severe ulcerated gastritis and H. pylori. Antibiotics were de-escalated and tailored to treat H. Pylori. Colonoscopy was performed given CT findings of circumferential stenosis within the ascending and transverse colon. Colonic and right orbit biopsies were consistent with metastatic SRCC. The patient was discharged home after the initial work up with future plans for orbital radiation, chemotherapy initiation, and repeat EGD. The number of cases of gastric SRCC has steadily increased over the last few decades, despite an overall decline in incidence in gastric cancer worldwide. SRCC is a distinct diffuse-type gastric adenocarcinoma based on its histological and clinical features. Patients typically present in advanced stages and carry a poor prognosis. Synchronous SRCC is rare, although the colon appears to be the most common synchronous cancer associated with gastric SRCC. Gastric SRCC has a predilection for metastasis to the peritoneum, lung, bladder, and in rare cases the optic nerve. H. Pylori may be associated with SRCC; treatment of H. Pylori improves mucosal healing and may aid in interventional therapies. This case represents a unique presentation of an advanced stage synchronous gastric and colonic SRCC.2661_A Figure 1. Periorbital edema of the right eye.2661_B Figure 2. Malignant ulcer with visible vessel and active bleeding. Friable mucosa surrounding ulcer.2661_C Figure 3. Orbital biopsy showing metastatic signet ring cell carcinoma (H&E, 400x).

Distinct Histopathologic and Molecular Alterations in Inflammatory Bowel Disease-Associated Intestinal Adenocarcinoma: c-MYC Amplification is Common and Associated with Mucinous/Signet Ring Cell Differentiation.

Chronic idiopathic inflammatory bowel disease (IBD) is a significant risk factor for the development of intestinal adenocarcinoma. The underlying molecular alterations in IBD-associated intestinal adenocarcinoma remain largely unknown. We compared the clinicopathologic and molecular features of 35 patients with 47 IBD-associated intestinal adenocarcinomas with a consecutive series of 451 patients with sporadic colorectal carcinoma identified at our institution and published data on sporadic colorectal carcinoma. c-MYC amplification was the most frequent molecular alteration identified in 33% of IBD-associated intestinal adenocarcinoma that is a significantly higher frequency than in sporadic colorectal carcinoma (8%) (P = 0.0001). Compared to sporadic colorectal carcinoma, IBD-associated intestinal adenocarcinomas more frequently demonstrated mucinous differentiation (60% vs 25%, P < 0.001) and signet ring cell differentiation (28% vs 4%, P < 0.001). Mucinous and signet ring cell differentiation were significantly associated with the presence of c-MYC amplification (both with P < 0.05). HER2 positivity (11%), KRAS exon 2 or 3 mutation (10%), and IDH1 mutation (7%) were less commonly observed in IBD-associated intestinal adenocarcinoma. There was an association between poor survival and HER2 status with 3 of 4 patients having HER2-positive adenocarcinoma dead of disease at last clinical follow-up; however, no statistically significant survival effect was identified for any of the molecular alterations identified. We demonstrate that IBD-associated intestinal adenocarcinomas have a high frequency of c-MYC amplification that is associated with mucinous and signet ring cell differentiation. Many of the identified molecular alterations have potential therapeutic relevance, including HER2 amplification, IDH1 mutation, and low frequency KRAS mutation.

Invasive Duct Carcinoma of the Breast With Dominant Signet-Ring Cell Differentiation: A Microsatellite Stable Tumor With Aggressive Behavior.

Invasive duct carcinoma, no special type (IDC, NST), of the breast with signet-ring cell differentiation is uncommon. This study was undertaken to describe the clinicopathologic characteristics of IDC, NST, with dominant signet-ring cell differentiation, and look for microsatellite instability in these tumors. Cases of IDC, NST, with dominant signet-ring cell differentiation, diagnosed over the past 2 years, were retrieved. Detailed clinical and pathologic analyses were performed. Immunohistochemistry was performed for estrogen receptor, progesterone receptors, Her-2 neu, Ki-67, E-cadherin, CK7, and CK20. Microsatellite instability was examined using immunohistochemistry for the 4 mismatch repair proteins: MLH1, MSH2, MSH6, and PMS2. Of the total 1646 cases of IDC, NST, only 5 cases showed dominant signet-ring cells (ranging from 70% to 100%) and strong E-cadherin positivity and were diagnosed as IDC, NST, with dominant signet-ring cell differentiation. The age ranged from 32 to 65 years. Two cases were of histologic grade 3 and the remaining cases were grade 2 tumors. Four patients had T2 tumor and 1 had T3 tumor. All cases had axillary lymph node metastasis and distant metastasis was present in 1 case. All cases were microsatellite stable. Signet-ring cell differentiation in IDC, NST, is rare and associated with a high histologic grade. Lymph node metastasis and distant metastasis are common, indicating an aggressive clinical behavior. Thus, they should be recognized separately as they may warrant aggressive management. However, these are microsatellite-stable tumors in contrast to signet-ring cell tumors of other organs.