Miwa Sada

Indications of Endoscopic Polypectomy for Rectal Carcinoid Tumors and Clinical Usefulness of Endoscopic Ultrasonography

PURPOSEThis study was designed to define the indications of endoscopic polypectomy for rectal carcinoid tumors and evaluate the diagnostic value of endoscopic ultrasonography.METHODSA total of 66 rectal carcinoid tumors treated at our hospital were analyzed histopathologically to clarify risk factors for metastasis. The depth of invasion was determined for 52 lesions examined by endoscopic ultrasonography, and the value of endoscopic ultrasonography for deciding whether a lesion is indicated for endoscopic polypectomy was assessed.RESULTSNone of the 57 lesions measuring ≤ 10 mm in diameter invaded the muscularis propria or had metastasis. Of nine lesions with a diameter of ≥ 11 mm, five invaded the muscularis propria and four had metastasis. A central depression was found in three of the lesions with metastasis. The depth of invasion of 49 lesions examined by endoscopic ultrasonography was limited to the submucosa; 3 lesions invaded the muscularis propria. The depth of invasion of all lesions was correctly diagnosed by endoscopic ultrasonography. Ninety-six percent of the lesions that had submucosal invasion with narrowing of the upper two-thirds of the third layer (submucosa) as evaluated by endoscopic ultrasonography could be completely resected by endoscopic polypectomy.CONCLUSIONSRectal carcinoid tumors that satisfy the following three conditions are indicated for local resection, including endoscopic polypectomy: a maximum diameter of ≤ 10 mm, no invasion of the muscularis propria, and no depression or ulceration in the lesion. Endoscopic ultrasonography also is useful for estimating the depth of invasion of rectal carcinoid tumors and for determining whether endoscopic polypectomy is indicated.

Dye spraying and magnifying endoscopy for dysplasia and cancer surveillance in ulcerative colitis

PURPOSEThe aim of this study was to investigate detection of dysplasia or colitic cancer with ulcerative colitis by use of magnifying endoscopic observation.METHODSFrom 1986 through 2000, ulcerative colitis was diagnosed and treated in 886 patients at Kitasato University East Hospital. Of the total, we studied 25 patients in depth: 14 who had dysplasia alone, 5 in whom cancer was diagnosed during follow-up after the detection of dysplasia, and 6 who had colitic cancer.RESULTSDysplasia was detected in 11 (3.2 percent) of 345 patients with extensive colitis and in 8 (3.7 percent) of 217 with left-sided colitis. Colorectal cancer was diagnosed in nine patients (2.6 percent) with extensive colitis and in two (0.9 percent) with left-sided colitis. Neither dysplasia nor colitic cancer was found in patients with proctitis-type colitis. Endoscopically, dysplasia and early cancer were characterized by granular or nodular protruding mucosa or by lowly protruding or flat mucosa, often associated with redness. Dye-spraying endoscopy was useful for detection. Magnifying endoscopy of ten regions of dysplasia (7 patients) and five early cancers (4 patients) showed IIIS to IIIL type pits or IV type pits. Biopsy of sites showing tumorous pits on magnifying endoscopy revealed dysplasia and early cancer. Observation of the pit pattern was found to be diagnostically useful.CONCLUSIONSDye spraying and magnifying endoscopy are useful for the detection, targeted biopsy, and diagnosis of dysplasia and colitic cancer in patients with ulcerative colitis.

Submucosal Fibrosis and Basic-Fibroblast Growth Factor-Positive Neutrophils Correlate with Colonic Stenosis in Cases of Ulcerative Colitis

Background and Aims: The frequency of benign stenosis in ulcerative colitis (UC) is low, reported as being 3.2–11.2%, with fibrosis in the submucosa or deeper pointed out as one of the causes. The aim of the present study was to assess stenosis in UC cases using immunostaining and to analyze differences between stenotic and nonstenotic cases, focusing on basic-fibroblast growth factor (b-FGF) expression and myofibroblasts. Methods: Totals of 9 stenotic and 17 nonstenotic UC cases were histopathologically examined and immunohistochemically stained for b-FGF, α-smooth muscle actin (α-SMA), CD34, CD68 and IL-6. To identify b-FGF-positive cells, double immunostaining for b-FGF and myeloperoxidase or CD68 was performed. Results: In addition to submucosal fibrosis, a significant increase of b-FGF-positive inflammatory cells and myofibroblasts was observed in stenotic portions. Most b-FGF-positive cells were also positive for myeloperoxidase, and a correlation between b-FGF-positive and total neutrophil counts was found. Conclusions: One of the major causes of stenosis in long-standing UC is fibrosis in the bowel wall, possibly induced by infiltrating inflammatory neutrophils producing b-FGF.

Clinical Study of the Relation between Mucosal Healing and Long-Term Outcomes in Ulcerative Colitis.

Background and Objectives. Mucosal healing (MH) is considered an important therapeutic goal in ulcerative colitis (UC). We evaluate the severity of intestinal inflammation and clarify the relation between MH and long-term outcomes. Methods. The study group comprised 38 patients with UC in clinical remission on total colonoscopy who were followed up for at least 5 years. Clinical remission was defined as a Mayo score of 0 for both stool frequency and rectal bleeding. Colonoscopic findings were evaluated into 4 grades according to the Mayo endoscopic subscore (MES). Results. During clinical remission, the MES was 0 in only 24% of the patients, 1 in 40%, 2 in 26%, and 3 in 10%. Seventy-six percent of the patients thus had active disease on colonoscopy. After initial colonoscopy, the cumulative rate of remission maintenance was 100% in MES 0, 1 in 93%, 2 in 70%, and 3 in 50% at 6 months and 78%, 40%, 10%, and 0%, respectively, at 5 years (P < 0.001). Conclusion. Many patients with UC in clinical remission have active lesions. Patients with a higher MES have a higher rate of recurrence. To improve long-term outcomes, an MES of 0 should be the treatment goal.

Different apoptotic activity and p21WAF1/CIP1, but not p27Kip1, expression in serrated adenomas as compared with traditional adenomas and hyperplastic polyps of the colorectum

PurposeSerrated adenomas (SAs), which include a wide spectrum of lesions, can be broadly divided into two subtypes: type I, closely mimicking hyperplastic polyps (HPs), and type II, unequivocal adenomatous tumor. Our preliminary findings showed clinicopathologic differences between them. The present study was conducted to investigate apoptotic activity and expression of the cell cycle regulator proteins p21WAF1/CIP1 and p27Kip1 in type I and II SAs, as compared with traditional adenomas (TAs) and HPs.MethodsApoptotic activity was estimated in hematoxylin-eosin stained specimens, and p21WAF1/CIP1 or p27Kip1 immunoreactivity was determined in 62 SAs (19 type I and 43 type II), 50 TAs and 19 HPs. The numbers (percentages) of apoptotic or immunoreactive cells were counted per 1,000 epithelial cells in equally separated crypt zones (upper, middle, and lower thirds).ResultsThe apoptotic activity in the middle, but not the upper or lower crypt zone was higher in type II SAs (median 0.2%, interquartile range 0.1–0.5%) than in HPs (0.1%, 0.1–0.2%, P<0.01), whereas it was lower in type I SAs (0.2%, 0.1–0.3%) than in TAs (0.5%, 0.2–0.6%, P<0.001). P21WAF1/CIP1 expression in the lower crypt zone was higher in both type I and type II SAs (19.8%, 7.0–33.2% and 20.4%, 3.9–47.8%, P<0.0001) than in TAs (1.2%, 0.6–5.2%), and a similar tendency was also observed for the middle crypt zone. p27Kip1 expression did not vary among the groups.ConclusionsThe differences in apoptotic activity and p21WAF1/CIP1 expression between SAs and TAs or HPs indicate that SA should be considered as a distinct subtype of colorectal neoplasm. The two subtypes of SA do not differ in these parameters despite specific clinicopathological features.

Mucosal remodeling in long-standing ulcerative colitis with colorectal neoplasia: Significant alterations of NCAM+ or α-SMA+ subepithelial myofibroblasts and interstitial cells

Evidence has been provided in ulcerative colitis (UC) that early genomic instability of both epithelial and stromal cells is important for colorectal tumorigenesis, as well as remodeling and morphological alterations of mucosal crypts. To clarify roles of stromal cells in tumor development in UC, the present study focused on heterogeneous phenotypes of subepithelial myofibroblasts and interstitial cells, in association with mucosal remodeling. To clarify the relationship of alterations to tumorigenesis, mucosa of resected rectae from patients with UC (n= 49) and sporadic cancer (n= 10) were analyzed on immunohistochemistry and also on immunoelectron microscopy. Heterogeneous phenotypes of neural cell adhesion molecule (NCAM)+ and/or α‐smooth muscle actin (α‐SMA)+ subepithelial myofibroblasts and interstitial cells were demonstrated, corresponding to colonic stellate cells. Decrease of NCAM+ subepithelial myofibroblasts and interstitial cells, and increase of α‐SMA+ interstitial cells were significant in UC with neoplasia as compared to without neoplasia. α‐SMA+ muscularis mucosae was significantly more thickened in tumor cases. Deposits of Massons trichrome+ and type III and I collagen in the muscularis mucosae and lamina propria appeared to increase in relation to the numbers of α‐SMA+ interstitial cells. Mucosal remodeling with alterations of NCAM+ or α‐SMA+ subepithelial and interstitial cells may play a critical role in UC‐associated tumorigenesis.

Multifocal granular cell tumors of the gastrointestinal tract : Immunohistochemical findings compared with those of solitary tumors

Granular cell tumors (GCT) are infrequently found in the gastrointestinal tract (GIT), and only four previous reports have described lesions occurring simultaneously in different sites. The present case of 11 GCT, located in the esophagus, stomach, colon and pericolic adipose tissue, occurred in a 50‐year‐old Japanese woman. All GCT appeared histologically benign and there was no sign of recurrence at 3 years after surgery. Immunohistochemical analysis and comparison between this case of multifocal GCT and six cases of solitary benign GCT of the GIT, which were taken from the files of the Department of Pathology at Kitasato University (1986–2000), demonstrated the follow‐ing:  (1) all diffusely expressed S‐100, DCC and bcl‐2, and (2) median labeling indices for Ki‐67, cyclin D1, p53 (Pab1801), and p21WAF1/CIP1 of 4%, 24%, 1% and 28%, respectively, for the multifocal tumors, and 3.5%, 23%, 1% and 29%, respectively, for the solitary lesions, with no significant difference between the two groups. Thus, the expression of cyclin D1 and p21WAF1/CIP1 may be involved in the tumorigenesis of both types of GCT. The present case emphasizes the need to evaluate the entire GIT when a single GCT is identified. Multifocal lesions should be treated conservatively by local excision because, as with the solitary tumors, they exhibit a benign biological behavior, consistent with their low Ki‐67 immunoreactivity.

Clinical role of endoscopic ultrasonography for the diagnosis of early colorectal cancer and selecting the treatment procedure

Background:  Accurate evaluation of the depth of tumor invasion, including the degree of submucosal invasion, is a prerequisite to selecting the treatment procedure for early colorectal cancer (CRC). The purpose of the present study was to evaluate the significance of endoscopic ultrasonography (EUS) for diagnosing the depth of invasion of early CRC and selecting the treatment procedure. We concurrently estimated the usefulness of three‐dimensional EUS (3‐D‐EUS) compared with that of conventional EUS.

Frequent Ki-ras mutations and transforming growth factor-alpha expression in adenocarcinomas of the small intestine: report of 7 cases.

Although the small intestine contains almost 90% of the mucosal surface area of the gastrointestinal tract, its incidence rate for cancer is only one fiftieth of that for the large intestine (1). Rapid turnover of small bowel mucosal cells is suggested as a possible reason for the low cancer rate, ie, partially transformed cells are shed before full carcinogenesis can occur (2, 3). However, this hypothesis has not been well investigated. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFα) are structurally related peptides that stimulate DNA synthesis and cell growth in various systems, including the gastrointestinal tract (4). Both EGF and TGFα recognize and compete for the same cell surface membrane receptor (EGF-R) through which they mediate their biological action (5). The vascular endothelial growth factor (VEGF) is a glycoprotein with specific actions on endothelial cells, mediating formation of new blood vessels from preexisting vasculature (6, 7). The role of these growth factors and related receptors regarding tumor growth and angiogenesis have been verified for colorectal carcinomas (8–11), but not fully investigated in small intestinal lesions.

Parathyroid hormone-related protein production by adenocarcinoma in Barrett's esophagus patient with dermatomyositis.

The link between polymyositis (dermatomyositis) with malignant tumors has been known for many years. In the largest series to date, about 10% of the patients with this muscle disease were found to have cancer, either at the same time or within 5 years of diagnosis (1). However, to our knowledge, only one case report of polymyositis with esophageal cancer has been published so far (2). Humoral hypercalcemia of malignancy (HHM) is one of the most common paraneoplastic syndromes (3, 4), parathyroid hormone-related protein (PTHrP) being regarded as the principal responsible agent (4–9). PTHrP is most commonly produced by squamous cell carcinomas, particularly of the lung, and by other epidermoid tissues, and only rarely by adenocarcinomas or neuroendocrine tumors (4, 5, 9). We report herein a patient with dermatomyositis and a Barrett’s esophagus-associated adenocarcinoma with neuroendocrine differentiation, who presented with HHM due to PTHrP produced by the tumor.