Metastatic pancreatic cancer with complete response to FOLFIRINOX treatment.

A 59-year-old woman presented with abdominal pain associated with nausea and night sweats. A large mass was found in the pancreatic tail and innumerable liver lesions were identified. Ultrasound-guided biopsy of a liver nodule confirmed moderately differentiated adenocarcinoma consistent with a pancreatobiliary primary. On FOLFIRINOX chemotherapy, subsequent CT scans showed shrinkage of the pancreatic mass and liver metastases. Her cancer antigen 19-9 (CA 19-9) normalised after 11 months. Oxaliplatin was discontinued due to peripheral neuropathy but she completed 37 cycles of FOLFIRI during which her pancreatic mass disappeared, liver lesions decreased in size and were subsequently deemed to be scar tissue by the radiologist. After 4 years of treatment, the patient agreed to a break from chemotherapy. Eighteen months afterwards, an MRI abdomen continues to demonstrate no visible pancreatic mass and the two remaining liver lesions, believed to be scar tissue, remain stable. Her CA 19-9 level remains normal. This appears to be a complete response to FOLFIRINOX/FOLFIRI chemotherapy in a patient with metastatic pancreatic cancer.

Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours.

BACKGROUND: Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells). METHODS: The expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray. RESULTS: CCT showed reduced Hes1/Elf3 and Sox9/Klf4 coupled with elevated Math1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higher Klf4 and similar Ngn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed a Notch signalling similar to adenocarcinoma. Mucinous tumours showed lower Elf3 than normal appendiceal epithelium and higher Math1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showed Notch signalling similar to other glandular tumours, but lower Klf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation. CONCLUSIONS: Wnt/secretory lineage protein and Notch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours.

Is pneumatosis cystoides intestinalis gas-distended and ruptured lymphatics? Reappraisal by immunohistochemistry.

CONTEXT: Pneumatosis cystoides intestinalis (PCI) is a condition with multiple gas-filled cysts within the bowel wall, associated with diverse background diseases. Its pathogenesis is still a mystery. Some previous observations scattered in the literature have suggested an association of the cystic spaces in PCI with the lymphatics. OBJECTIVE: To further investigate whether PCI results from the ballooning of gas-filled lymphatic channels. DESIGN: We did immunostaining of podoplanin, a mucoprotein preferentially expressed in lymphatic endothelial cells, in 13 cases (8 men, 5 women; age range, 18-80 years) of PCI. Ten cases were diagnosed in resected segments of bowel and 3 in biopsies. Pneumatosis was seen in the right side of the colon (9 cases), transverse colon (1 case), sigmoid colon (1 case), and small bowel (2 cases). In addition, immunostaining for CD31, calretinin, WT1, CD68, smooth muscle actin, desmin, vimentin, and cytokeratins was also performed for comparison and correlation. RESULTS: A strong immunopositivity of podoplanin was seen in a condensed linear structure in the pericystic interstitium in 100% of the cases, but was not seen in the overlying giant and flat cells that were all CD68-positive histiocytes. Meanwhile, the podoplanin-expressing structure was negative for calretinin and WT1, which ruled out the possible mesothelial origin. There were coexistent variable immunopositivity of smooth muscle actin, which suggests an admixture of myofibroblasts. These findings indicated that the PCI cases were gas-distended lymphatics with the lymphatic epithelium ruptured and embedded in the reactive histiocytes and giant cells. CONCLUSION: Our findings support the lymphatic theory about the pathogenesis of PCI.

Interobserver variability in assessing dysplasia and architecture in colorectal adenomas: a multicentre Canadian study.

AIMS: Following the introduction of colorectal cancer screening programmes throughout Canada, it became necessary to standardise the diagnosis of colorectal adenomas. Canadian guidelines for standardised reporting of adenomas were developed in 2011. The aims of the present study were (a) to assess interobserver variability in the classification of dysplasia and architecture in adenomas and (b) to determine if interobserver variability could be improved by the adoption of criteria specified in the national guidelines. METHODS: An a priori power analysis was used to determine an adequate number of cases and participants. Twelve pathologists independently classified 40 whole-slide images of adenomas according to architecture and dysplasia grade. Following a wash-out period, participants were provided with the national guidelines and asked to reclassify the study set. RESULTS: At baseline, there was moderate interobserver agreement for architecture (K=0.4700; 95% CI 0.4427 to 0.4972) and dysplasia grade (K=0.5680; 95% CI 0.5299 to 0.6062). Following distribution of the guidelines, there was improved interobserver agreement in assessing architecture (K=0.5403; 95% CI 0.5133 to 0.5674)). For dysplasia grade, overall interobserver agreement remained moderate but decreased significantly (K=0.4833; 95% CI 0.4452 to 0.5215). Half of the cases contained high-grade dysplasia (HGD). Two pathologists diagnosed HGD in ≥75% of cases. CONCLUSIONS: The improvement in interobserver agreement in classifying adenoma architecture suggests that national guidelines can be useful in disseminating knowledge, however, the variability in the diagnosis of HGD, even following guideline review suggests the need for ongoing knowledge-transfer exercises.

Solitary lesions with fibrosis and increased IgG4+ plasma cells: part of the expanding spectrum of IgG4-related disease or a nonspecific inflammatory response?

We assessed 6 cases acquired during routine surgical sign-out for IgG4-related disease (IRD) according to criteria from a recent consensus meeting. These cases fulfilled the morphologic criteria-that is, dense lymphoplasmacytic infiltrates, IgG4:IgG ratio greater than or equal to 0.4, and fibrosis (storiform in 4 cases-but were associated with malignancy or did not fulfill the criteria for a new site. These criteria include increased serum IgG4 (normal in the majority of IRD) and a response to glucocorticoids, which is not appropriate treatment for resectable lesions as in our cases. Until more is known about the natural history of the disease, we propose that the possibility of an early, localized, or forme fruste of IRD should be considered and that cases associated with malignancy should at least be documented. Although we acknowledge the value of the consensus criteria, their strict application may result in missed opportunities to study the disease.

Appendiceal goblet cell carcinoid and mucinous neoplasms are closely associated tumors: lessons from their coexistence in primary tumors and concurrence in peritoneal dissemination.

BACKGROUND: Goblet cell carcinoid (GCC) and appendiceal mucinous neoplasms (AMNs) are considered as different appendiceal tumors. Coexistence of both tumors was occasionally noted. We further observed the concurrence in both primary tumors and their peritoneal dissemination, that is, peritoneal carcinomatosis (PC) including pseudomyxoma peritonei (PMP). METHODS: Review of our 10-year file identified two subgroups of cases with such concurrence. Group 1 is 14 cases of PC/PMP treated by surgical cytoreduction. Morphologic components of GCC, low-grade mucinous neoplasm (LMN), mucinous adenocarcinoma (MCA), and non-mucinous adenocarcinoma (NMCA) were identified separately in different organs/tissues. Group 2 is eight cases of localized primary tumors of appendix and ileocecal junction. RESULTS: In Group 1, primary tumors (11 GCC, 1 GCC + LMN, 1 MCA, 1 NMCA) were identified in appendix (13) and in rectum (1). Further review identified mixed morphologic components in 7/12 GCC cases, including GCC + LMN (2), GCC + MCA (2), GCC + NMCA (1), and GCC + MCA + NMCA (2). Over peritoneal dissemination, GCC and/or other components were coexistent at different sites and in variable combinations. In Group 2, primary tumors were initially diagnosed as GCC (7) and MCA (1). Further review identified mixed components in all cases, including GCC + LMN (3), GCC + LMN + MCA (3), GCC + MCA + NMCA (2). CONCLUSIONS: GCC may present as a component mixed with AMNs and even with conventional adenocarcinoma in both primary tumors and metastatic lesions. AMN in any given single case may show a wide morphologic spectrum. GCC and AMN may share a common tumor stem cell with potential of multiple lineage differentiations.

Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice.

While there is evidence that specific T cell populations can promote the growth of established tumors, instances where T cell activity causes neoplasms to arise de novo are infrequent. Here, we employed two conditional mutagenesis systems to delete the TGF-ß signaling pathway component Smad4 in T cells and observed the spontaneous development of massive polyps within the gastroduodenal regions of mice. The epithelial lesions contained increased levels of transcripts encoding IL-11, IL-6, TGF-ß, IL-1ß, and TNF-α, and lamina propria cells isolated from lesions contained abundant IL-17A+CD4+ T cells. Furthermore, we found that Smad4 deficiency attenuated TGF-ß-mediated in vitro polarization of FoxP3+CD4+ T cells, but not IL-17A+CD4+ T cells, suggesting that the epithelial lesions may have arisen as a consequence of unchecked Th17 cell activity. Proinflammatory cytokine production likely accounted for the raised levels of IL-11, a cytokine known to promote gastric epithelial cell survival and hyperplasia. Consistent with IL-11 having a pathogenic role in this model, we found evidence of Stat3 activation in the gastric polyps. Thus, our data indicate that a chronic increase in gut Th17 cell activity can be associated with the development of premalignant lesions of the gastroduodenal region.

Goblet cell carcinoids at extraappendiceal locations of gastrointestinal tract: an underrecognized diagnostic pitfall.

BACKGROUND: Goblet cell carcinoid (GCC) is a clinicopathologically distinctive tumor that typically arises in appendix and metastasizes frequently. Although rare cases of ostensibly primary extraappendiceal GCC (EGCC) have been reported, the distinction from extraappendiceal metastasis of occult appendiceal primary may be problematic and has not been dealt with systematically in literature. METHODS: We reviewed our combined experience with EGCC at four North American hospitals and reevaluated all EGCC cases published in literature. RESULTS: We encountered 16 cases that were initially reported as EGCC. Five cases presented with disseminated abdominopelvic spread, nine cases with mass lesions in stomach, ileum, cecum, ascending colon, hepatic flexure, sigmoid, and rectum. One case was found incidentally in an ascending colon adenomatous polyp. A negative appendix was confirmed in 2 (12.5%) cases, whereas a primary appendiceal GCC was discovered in 4 (25%) cases at a later date, and appendix was not available for review in 10 cases (62.5%). Of 10 cases of EGCC found in literature, the tumor sites included stomach, duodenum, jejunum, ileum, cecum, splenic flexure, and rectum. Primary appendiceal tumor was excluded histologically in one (10%), grossly in three (30%), and not at all in six (60%). Nine of our cases were initially misdiagnosed as signet-ring cell adenocarcinomas. CONCLUSIONS: True EGCC is extremely rare. GCC found at locations other than appendix are most likely extraappendiceal presentations of appendiceal primary. A thorough review of the pathologic status of appendix should be a mandatory diagnostic criterion and should always be documented in the pathology reports.

Juvenile polyposis of the stomach--a novel cause of hypergastrinemia.

BACKGROUND: A 38-year-old female presented with a 3-year history of postprandial abdominal pain, refractory nausea, vomiting and hematemesis. She appeared malnourished and her symptoms were refractory to previous treatment with acid-suppressive drugs, prokinetics and antiemetics. Her medical history was significant for a diagnosis of juvenile polyposis syndrome at the age of 14 resulting in a transverse colectomy, and a diagnosis of Crohn's disease in her residual colon at the age of 35 resulting in a total colectomy. INVESTIGATIONS: Physical examination, blood analysis, esophagogastroduodenoscopy with biopsy, abdominal endoscopic ultrasound, abdominal CT scan, MRI, 24 h urine analysis, MIBG scintigraphy, ocreotide scintigraphy, fluorodeoxyglucose-PET scan and genetic testing for defined polyposis syndromes (SMAD4, BMPR1A). DIAGNOSIS: Juvenile polyposis syndrome with outlet obstruction of the stomach and excessive hypergastrinemia. MANAGEMENT: Continuous acid-suppressive therapy, prokinetic therapy and total parenteral nutrition. Repetitive endoscopic polypectomy (also known as debulking) was performed twice and was followed by gastrectomy with duodenoesophageal anastomosis.

Clinical experience of the multimodality management of anaplastic thyroid cancer and literature review.

Anaplastic Thyroid Carcinoma (ATC) is a rare thyroid tumor with a very aggressive clinical course. The following is a report of five patients with inoperable locally advanced disease treated at our institution using multimodality management consisting of chemotherapy and hyperfractionated accelerated radiotherapy. A flow diagram with management recommendations for inoperable ATC is suggested.

Autoimmune pancreatitis associated with renal lesions mimicking metastatic tumours.

Autoimmune pancreatitis is a chronic inflammatory disorder that is often misdiagnosed as pancreatic cancer. Since autoimmune pancreatitis is benign and responds to steroid management, it is important to diagnose it to avoid unnecessary surgical intervention. We describe a novel case of IgG4-associated autoimmune pancreatitis presenting with tubulointerstitial nephritis as renal lesions mimicking metastatic tumours but with no change in renal function.

Sessile serrated polyp mimicry in patients with solitary rectal ulcer syndrome: is there evidence of preneoplastic change?

CONTEXT: Solitary rectal ulcer syndrome (SRUS) is associated with erythema and ulceration of the rectal wall. Serrated lesions of the colon are divided into conventional hyperplastic polyps and a new set of lesions that are variably called sessile serrated polyps (SSPs) and sessile serrated adenomas. The SSPs are epithelial proliferative lesions that appear to act as a unique pathway to colorectal carcinogenesis. No association between SRUS and SSPs has been previously reported. OBJECTIVE: To assess a possible association between SRUS and morphologic features that mimic SSPs. DESIGN: Twenty-six patients with SRUS, who presented to our institution between January 1, 1999, and November 14, 2004, were retrospectively reviewed for SSP-type morphologic features by 3 pathologists. Ki-67 and hMLH1 immunohistochemical stains were used. Control tissues included 10 conventional left-sided hyperplastic polyps, 10 right-sided large SSPs, 7 adenocarcinomas with known loss of hMLH1 gene expression, and 4 normal human tonsil tissues. RESULTS: Ten (38%) of 26 SRUS specimens demonstrated histologic features consistent with SSPs. These features included exaggerated serration within the lower crypt compartments, crypt branching, hypermucinous appearance of epithelium, and horizontal extension of crypt bases along the muscularis mucosa. All 10 cases of SRUS had positive basal Ki-67 staining in 10% to 20% of cells. Two (20%) of the 10 cases demonstrated focal superficial loss of hMLH1 mismatch repair gene expression within areas of serrated morphologic features. One hyperplastic polyp superimposed on SRUS showed a reduced number of surface epithelial cells that express hMLH1 protein. CONCLUSIONS: Up to 38% of patients with SRUS have histologic changes that mimic SSPs. More importantly, 20% of these serrated lesions were found to have focal loss of hMLH1 gene expression, indicating a potential of preneoplastic change. This phenomenon may reflect an increased propensity for neoplastic progression in response to repeated trauma and repair process in certain cases of SRUS.

Verrucous carcinoma of the esophagus eluding multiple sets of endoscopic biopsies and endoscopic ultrasound: a case report and review of the literature.

A 56-year-old woman was noted to have a 5 cm to 6 cm long, irregular narrowing of the distal esophagus on an upper gastrointestinal series. Initial endoscopy revealed a polypoid mass in the distal esophagus and concurrent endoscopic ultrasound revealed changes typical of inflammation but no evidence of an obvious neoplastic process. Repeated biopsies revealed only inflammation with no evidence of malignancy. Only after prolonged acid suppression did biopsies reveal verrucous carcinoma of the esophagus. The patient underwent a trans-hiatal esophagectomy and has remained well with no evidence of progression since. Verrucous carcinoma is a rare variant of squamous cell carcinoma, taking on a papillary or warty appearance grossly. Histological diagnosis may be difficult because this tumour typically shows no high-grade dysplasia. Therefore, diagnosis can be challenging, often requiring multiple sets of endoscopic biopsies due to the overlying hyperkeratotic layer. Of the 20 cases that have been reported, this is the second to provide an endosonographic description and the first to describe a change in endoscopic appearance with acid suppression.

Angiosarcoma of the colon and rectum: report of a case and review of the literature.

Angiosarcoma is a malignancy that occurs rarely in the gastrointestinal tract. We present a case of a 77-year-old male who had rectal bleeding and obstructive bowel symptoms. A large near-obstructing mass was seen endoscopically, but biopsies were inconclusive. A CT scan showed a large sigmoid lesion, and the patient had surgical resection. A large hemorrhagic-appearing tumor was found at operation. Angiosarcoma of the sigmoid colon was diagnosed on histologic examination. After colonic resection, the patient rapidly developed numerous liver metastases and died six months later. A review of the literature reveals only 12 other reported cases of colorectal angiosarcoma; 62 percent of these patients died within one year of surgical resection. The role of adjuvant radiation and/or chemotherapy is unclear. In conclusion, colorectal angiosarcomas are rare tumors that behave very aggressively, and the outcome is generally poor.