Adenomatous Areas Research Articles

Molecular characteristics of colorectal hyperplastic polyp subgroups.

The importance of hyperplastic polyps during colorectal carcinogenesis is appreciated related to the understanding of serrated pathway. The morphologic subtypes of hyperplastic polyps in carcinogenesis and the nomenculature of lesions with both hyperplastic and adenomatous areas are controversial. We aimed to reveal the molecular properties of hyperplastic polyp subtypes and the molecular changes in polyps containing both hyperplastic and adenomatous areas. Matherial and Methods: 49 hyperplastic polyps [19 microvesicular (MVHP), 19 goblet-rich (GRHP), 11 mucin-poor (MPHP)] and 10 mixed hyperplastic and adenomatous polyps were analysed for KRAS, BRAF mutations and MSI with real-time PCR. 68,4% of MVHPs and 81% of MPHPs which were localized in right colon had BRAF mutations. While none of the GRHPs showing a KRAS mutation with a rate of 73% was localized in the ascending colon, 63% of them were localized in the rectosigmoid area. In five (50%) of the mixed polyps, KRAS mutation was detected both in the hyperplastic and adenoma components. There was no BRAF mutation in any of the mixed polyps. However, in two cases, the hyperplastic component was MSI-H and the adenoma area was MSS. Hyperplastic polyps, even if smaller than 5 mm, are precancerous lesions bearing different mutations. GRHPs with predominant KRAS mutations and MVHPs and MPHSs with predominant BRAF mutations are precancerous. Although the molecular investigations for HPP/SP are not necessary the morphological subtyping should be included if the case is diagnosed with HPP/SP as it will be useful for attracting the gastroenterologist's attention.

Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors.

Recent studies revealed that colorectal tumors are composed of genetically diverse subclones. We aimed to clarify whether the surface microstructures of colorectal tumors are associated with genetic intratumoral heterogeneity (ITH). The surface microstructures (pit patterns) of colorectal tumors were observed using magnifying endoscopy, and biopsy specimens were obtained from respective areas when tumors exhibited multiple pit patterns. A total of 711 specimens from 477 colorectal tumors were analyzed for BRAF, KRAS and TP53 mutations using pyrosequencing and direct sequencing. A panel of cancer-related genes was analyzed through targeted sequencing in 7 tumors. Colorectal tumors with multiple pit patterns exhibited more advanced pit patterns and higher frequencies of KRAS and/or TP53 mutations than tumors with a single pit pattern. In tumors with multiple pit patterns, mutations were observed as public (common to all areas) or private (specific to certain areas), and private KRAS and/or TP53 mutations were often variable and unrelated to the pit pattern grade. Notably, invasive CRCs frequently exhibited public TP53 mutations, even in adenomatous areas, which is indicative of their early malignant potential. Targeted sequencing revealed additional public and private mutations in tumors with multiple pit patterns, indicating their single clonal origin. Our results suggest intratumoral pit pattern variation does not simply reflect the process of colorectal tumor evolution, but instead represents genetically diverse subclones, and this diversity may be associated with malignant potential.

A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer

BackgroundStepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC). These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC.Methods and FindingsWe analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β) growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5%) but not in tumors with downregulated but non-alternating PTEN expression (14.3%). There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.ConclusionsIn conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways. This bottleneck-like zone is usually followed by the emergence of invasive tumors with intact PTEN expression but dysregulated TP53 and uniformly high proliferation rates.

Abstract 3864: A transition zone showing highly discontinuous or rapidly oscillating levels of stem cell and proliferation markers characterizes the development of colorectal cancer

Abstract Background: Stepwise acquisition of genetic changes characterize the development of colorectal cancer (CRC). These mutational events are correlated with discrete morphologic transitions from hyperplastic to adenomatous areas followed by in situ transformation and finally invasive carcinoma. The genetic drivers for each stage of this process, however, have not been fully established and can be confounded by tumor heterogeneity. The goal of this study was to identify easily assessed biomarkers of key morphogenetic transitions in CRC. Methods and Findings: We analyzed the pattern of proliferation and expression of growth regulatory and stem cell markers across distinct morphologic transition zones in 726 cases of CRC. In cases with preserved adenoma-carcinoma morphologic transitions, we identified a characteristic zone of adenomatous epithelium, often located immediately adjacent to and extending into the invasive component, that showed rapidly oscillating intraglandular stretches of Ki-67+ and Ki-67- cells. This pattern correlated with oscillating expression of other cell cycle mediators and the growth regulators PTEN and SMAD4. These multifocal stretches of adenomatous epithelium showed alternating abrupt positive/negative expression boundaries. These zones also demonstrated similar abrupt intragland oscillations in the levels and/or subcellular localization of multiple cancer stem cell (CSC) markers including beta-catenin/CTNNB1, MGMT and CD44. In contrast, the expression levels of most of these markers were largely homogenous in the proximal adenomatous and deeper invasive carcinoma surrounding the transitional region. This CSC-like transitional zone, as detected by PTEN IHC, was prominent in 50/726 of all CRC (6.9%) but at least focally present in 97/201 (48.2%) cases with intact adenoma-carcinoma junctions. Genomic microarray (OncoScan HD) and mutation analysis (Ampliseq) on CRC with prominent CSC-like expansions demonstrated complex genomic changes in 12/18 (66.7%) with a similar frequency of KRAS, BRAF and CTNNB1 mutations as expected in unselected CRC cases. The transition zones in these cases also frequently demonstrated unstable genomes from cell-to-cell (as assessed by FISH) indicating high genetic instability in these areas. Conclusions: We show that multiple immunohistochemical markers, including PTEN, SMAD4, CD44 and CTNNB1, highlight a localized CSC-like transition zone of rapidly alternating quiescent/proliferative adenomatous epithelium in primary CRC tumors. This transition zone often begins in pre-invasive adenomatous epithelium adjacent to invasive tumor areas that have more uniform proliferation and more homogeneous genetic and expression profiles. This easily assessed phenomenon appears to represent a commonly occurring genetically unstable forerunner or transitional stage in CRC evolution. Citation Format: Kevin J. Arvai, Ya-Hsuan Hsu, Lobin A. Lee, Dan Jones. A transition zone showing highly discontinuous or rapidly oscillating levels of stem cell and proliferation markers characterizes the development of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3864. doi:10.1158/1538-7445.AM2014-3864

Spiradenoma With Marked Adenomyoepitheliomatous Features

To the Editors: In 2008, we reported a series of 5 cases of spiradenoma and 1 case of spiradenocylindroma that, in addition to areas of a conventional growth, manifested an adenomatous component consisting of compactly situated well-developed glands having small round lumens lined by inner pale to eosinophilic cells and surrounded by an outer well-formed peripheral layer of myoepithelial cells.1 Lymphocytes, an essential constituent of a spiradenoma, were markedly diminished or absent in the adenomatous areas. In 4 of those 6 cases, the adenomatous component was a minor but significant portion of the tumors, but in 2 cases, it was quite prominent, comprising approximately 20% of the tumor area.1 We have recently encountered a case of spiradenoma in a 60-year-old male patient located on the right temple with an unduly marked adenomatous (adenomyoepitheliomatous) moiety, which clearly dominated over the conventional portion of the neoplasm, comprising in as much as 75% (Fig. 1A, B). As in the original neoplasms, each glandular structure was surrounded by a well-developed peripheral layer of myoepithelial cells, which stained for S-100 protein and alpha smooth muscle actin (Fig. 1C, D). These areas and myoepithelial differentiation were so prominent that one can speak of “adenomyoepitheliomatous” areas instead of a mere “adenomatous” component. The adenomyoepitheliomatous areas were identical to those seen in adenomyoepitheliomas in various organs. Apart from the prominence of the adenomyoepitheliomatous compartment, the present case manifested some other features that were neither observed in our previous report nor in that of Michal2 who described the first occurrence of well-developed glands in spiradenoma. Namely, albeit usually being simple with round lumina, some glandular structures in the present case manifested a more complex appearance, with intraluminal bridging or, occasionally, cribriform features (Fig. 1E, F). Additionally, there were multiple foci with squamous metaplasia and intraglandular clear cell metaplasia (Fig. 1G), and in some areas, it was evident that the squamous metaplastic epithelium is closely associated with the glandular elements.FIGURE 1: Spiradenoma (A) with a prominent and dominant adenomyoepitheliomatous component highlighted by alpha smooth muscle actin (B); glands with a well-developed peripheral myoepithelial cell layers adjacent to conventional areas of spiradenoma (C); peripheral myoepithelial cell layers highlighted by alpha smooth muscle actin (D); occasional glands demonstrating intraluminal bridging (E) and a cribriform appearance (F); and areas with squamous metaplasia. G, Clear cell change within some lumina.This case with unduly prominent adenomyoepitheliomatous differentiation further underscores diagnostic difficulties that may be caused by an unusual example of spiradenoma. It was sent in consultation with differential diagnostic considerations that included, among others, malignant transformation. Indeed, some malignant tumors arising within preexisting spiradenoma may manifest similar adenomatous areas, including adenocarcinoma in situ or invasive adenocarcinoma.3 In our original series on spiradenomas with an adenomatous component, there was one case with clearly atypical adenomatous component, which together with subsequent observations of invasive adenocarcinoma arising from benign spiradenoma suggests that one of the pathways of malignant transformation in spiradenomas may be via a sequence of adenomatous and atypical adenomatous change, adenocarcinoma in situ, and, ultimately, invasive adenocarcinoma.3 Denisa Kacerovska, MD, PhD Dmitry V. Kazakov, MD, PhD Sikl's Department of Pathology, Medical Faculty Hospital, Charles University, Pilsen, Czech Republic Heinz Kutzner, MD, PhD Dermatohistopathologische Gemeinschaftspraxis, Friedrichshafen, Germany Michal Michal, MD Sikl's Department of Pathology, Medical Faculty Hospital, Charles University, Pilsen, Czech Republic, Bioptical Laboratory, Pilsen, Czech Republic

Congenital Hyperinsulinism in Brazilian Neonates: A Study of Histology, KATP Channel Genes, and Proliferation of β Cells

Congenital hyperinsulinism (CHI) is a rare pancreatic β-cell disease of neonates, characterized by inappropriate insulin secretion with severe persistent hypoglycemia, with regard to which many questions remain to be answered, despite the important acquisition of its molecular mechanisms in the last decade. The aim of this study was to examine pancreatic histology, β-cell proliferation (immunohistochemistry with double staining for Ki-67/insulin), and β-cell adenosine triphosphate-sensitive potassium channels genes from 11 Brazilian patients with severe medically unresponsive CHI who underwent pancreatectomy. Pancreatic histology and β-cell proliferation in CHI patients were compared to pancreatic samples from 19 age-matched controls. Ten cases were classified as diffuse form (D-CHI) and 1 as focal form (F-CHI). β-cell nucleomegaly and abundant cytoplasm were absent in controls and were observed only in D-CHI patients. The Ki-67 labeling index (Ki-67-LI) was used to differentiate the adenomatous areas of the F-CHI case (10.15%) from the "loose cluster of islets" found in 2 D-CHI samples (2.29% and 2.43%) and 1 control (1.54%) sample. The Ki-67-LI was higher in the F-CHI adenomatous areas, but D-CHI patients also had significantly greater Ki-67-LI (mean value = 2.41%) than age-matched controls (mean value = 1.87%) (P = 0.009). In this 1st genetic study of CHI patients in Brazil, no mutations or new polymorphisms were found in the 33-37 exons of the ABCC8 gene (SUR1) or in the entire exon of the KCNJ11 gene (Kir 6.2) in 4 of 4 patients evaluated. On the other hand, enhanced β-cell proliferation seems to be a constant feature in CHI patients, both in diffuse and focal forms.

Preneoplastic lesions in gallbladder cancer

Gallbladder cancer is an uncommon disease except in countries like Chile and areas of India and Japan. The knowledge regarding the etiology and mechanisms through which this neoplasia is developed is significantly less compared to other malignant tumors. The epithelial lesions involved in gallbladder carcinogenesis are dysplasia and adenomas that represent two biologically distinct carcinogenetic models. Dysplasia progresses to carcinoma in situ (CIS) and subsequently becomes invasive. Over 80% of invasive gallbladder cancers present areas adjacent to the CIS and epithelial dysplasia. Other authors have demonstrated adenomatous areas in carcinomas, or malignant transformation in an adenoma. The low incidence of gallbladder adenomas (0.14% of cholecystectomies) and the presence of adenomatous remnants in the neighboring mucosa to early carcinomas in less than 3% of the cases suggest the limited importance of this carcinogenic pathway. Epithelial dysplasia which is not associated with gallbladder cancer is observed in approximately 1% of cholecystectomies for symptomatic lithiasis. Metaplasia, dysplasia, and CIS are present in the mucosa adjacent to the cancer in 66%, 81.3%, and 69%, respectively. The average ages of patients with dysplasia not associated to cancer (51.9 years), early carcinomas (56.8 years), and advanced carcinomas (62.9 years) demonstrate a gradient which suggests the progression of these lesions. From the morphological point of view, the dysplasia-carcinoma sequence is the most plausible carcinogenic pathway for gallbladder cancer, a process which would require a period of approximately 10 years.

Poliposis múltiple juvenil no familiar: Caso clínico

We report a 15 years old girl presenting with severe hematochezia with secondary anemia and hemodynamic decompensation, rectal prolapse and spontaneous anal elimination of polyps. She had no family history of polyposis and a search for the disease in her close relatives was negative. A complete diagnostic work up did not find polyps in other segments of the digestive tract. Colonoscopy showed more than 200 polyps between the cecum and the rectum. Pathological analysis confirmed the presence of retention polyps with adenomatous areas and mild atypia. The patient was subjected to a proctocolectomy with ileal pouch and sphincteric preservation, using a mechanical suture. Postoperative evolution was uneventful and after 24 months of follow up, the patient is asymptomatic, with two stool movements per day and without incontinence.

Angiogenesis and p53 expression in the colorectal adenoma-carcinoma sequence.

Angiogenesis, the formation of new vessels, is essential for tumor growth and metastasis. Mutations of p53 tumor suppressor gene are frequent and play an important role in colorectal oncogenesis. A role of p53 as an angiogenesis inhibitor has also been proposed. We evaluated angiogenesis and p53 expression in 16 hyperplastic polyps, 35 solitary tubular and tubulovillous adenomas, and 47 cases of sporadic colorectal carcinomas arising on the basis of preexisting adenomas, with standard immunohistochemical techniques. The mean microvessel density (MVD) in carcinomas was significantly higher compared with the respective adenomatous part of the same tumor (27.9 vs. 7; P=0.0001). Linear regression analysis of MVD between cancerous and adenomatous areas showed a significant correlation (P = 0.0001, r = 0.56), raising the possibility that carcinomas arising from better vascularized adenomas might show increased vascularity. The MVD was significantly higher in stage C compared with stage A cases (P=0.04). p53 positivity was detected in 26 of 47 cancerous (55%) and in 14 of 47 adenomatous areas (30%; P = 0.0002). All carcinomas arising from p53-positive adenomas were also p53 positive. p53 positivity associated with a higher MVD in adenomas (P = 0.02), but not in carcinomas (P = 0.78). We conclude that angiogenesis and p53 play a critical role in colorectal neoplasia, and the process of malignant transformation in tumors arising from highly angiogenic adenomas, particularly those carrying p53 mutations, is accelerated with rapid tumor progression from stage to stage, indicating a more aggressive tumor phenotype.

Carcinoma of the Ampulla of Vater Associated With or Without Adenoma: A Clinicopathologic Analysis of 198 Cases With Reference to p53 and Ki-67 Immunohistochemical Expressions

Adenomatous areas are found frequently within or in the vicinity of carcinoma of the ampulla of Vater. This makes definite diagnosis difficult in the preoperative examination. The adenoma–carcinoma development hypothesis is generally accepted for colorectal tumors. Recently, a genetic alteration model during colorectal tumor development has attracted much attention, leading to various studies. We studied clinicopathologic features, prognostic factors, and the alteration of the p53 tumor suppressor gene using p53 immunohistochemical staining in pure adenomas, pure carcinomas, and carcinomas with adenomatous areas. A proliferative activity of the tumors using Ki-67 was also evaluated. Nine cases of pure adenoma and 198 cases of carcinoma of the ampulla of Vater were selected for this study. Among the 198 cases of the carcinoma, 83 cases (42%) had adenomatous areas. Positivity of p53 immunohistochemical staining was 0% in pure adenomas, 36% in the adenomatous areas of carcinomas with adenomatous areas and 62% in the carcinomatous areas of carcinomas with adenomatous areas, and 56% in pure carcinoma. Accumulation of p53 protein and the Ki-67 labeling index revealed no significant difference in prognosis. The clinicopathological factors examined were as follows: degree of invasion of the surrounding tissue, such as duodenal wall; pancreatic parenchyma; the presence or absence of lymphatic permeation; venous invasion; perineural invasion; the presence of regional lymph node metastasis; and TNM stage. Each of the clinicopathological factors showed a significant difference. Multivariate analysis revealed strong predictors for a worse prognosis: presence of lymphatic permeation, invasion of the pancreas, and perineural invasion. In conclusion, our results are consistent with the adenoma–carcinoma development hypothesis. It would seem that the molecular events leading to p53 accumulation in neoplasms of the ampulla of Vater occur relatively late during the oncogenetic process. Moreover, we think it may be useful to refer to the p53 overexpression in the diagnosis of ampullary tumors.

Mutations associated with carcinomas arising from pleomorphic adenomas of the salivary glands

Pleomorphic adenoma (PA) is the most common benign tumor of salivary glands. Carcinomas in pleomorphic adenomas (CPAs) may arise by malignant transformation of the epithelial components of PAs. Occasionally, transitional zones containing cells with histological features intermediate between those of the benign PA and carcinomatous components of CPA are identified. After careful microdissection of archival microslides, the authors studied 12 cases of CPAs and their attendant adenomatous and transitional areas for mutations in the p53, RB, and K- ras genes, and at chromosomal loci 5q and 9p. The authors failed to find mutations in the K- ras gene or 9p locus. A relatively high rate of mutations (loss of heterozygosity [LOH] and microsatellite alterations) at the p53 gene were detected in CPAs (58%), and at somewhat lower frequencies at the RB gene (33%) and chromosomal location 5q (17%). Mutational frequency in the associated transitional and adenomatous areas were slightly lower than in the corresponding CPAs. No mutations were detected in ade nomatous or transitional areas unless they also were present in the corresponding CPAs. Mutations of these three genes were absent in four cases of CPA, and in seven PAs without malignant change. These findings indicate that most CPAs arise from adenomas as the result of mutations in the three genes, especially p53. In addition, other, as yet unidentified genes may also be involved both in the development of PA and in its malignant progression to CPA. Mutational analysis of PAs may provide information of prognostic importance.

Pathologic and ultrastructural findings in sheep in Morocco with naturally occuring jaagsiekte (sheep pulmonary adenomatosis)

Jaagsiekte was studied in the lungs of 85 sheep of Sardi and mixed breeds ranging from 7 months to 8 years of age. Lungs were examined grossly, histologically and, in five cases, by transmission electron microscopy. Lesions in lungs with jaagsiekte were described: they consisted of multiple focal to coalescent neoplastic nodules. Microscopic architecture of the neoplasms was similar in all cases, and lesions were seen as foci of cells arranged in glandular-like patterns (acinar and/or papillary). Intraalveolar fibrosis was prominent in many cases, specially in chronic ones, and alveolar macrophages were consistently found within alveolar spaces. In some cases (38/85), nodules or masses of myxomatous-like tissue were seen in the vicinity of adenomatous areas. Associated verminous pneumonia, hydatid cysts, and secondary bacterial bronchopneumonia were frequently encountered. Ultrastructurally, the proliferating neoplastic cells appeared to result from the transformation of Type II pneumocytes. Neither metastatic lesions nor viral inclusions were observed during this investigation. Sheep in the present study were not tested for antibodies to ovine lentivirus, maedi/visna. This descriptive study provides a morphological background necessary for routine differentiation and indicates the necessity of initiating studies on viral etiology and pathogenesis of jaagsiekte in Morocco.

Ras‐family gene mutations in neoplasia of the ampulla of vater

Mutations in the first and second exons of Ha-, Ki- and N-ras oncogenes were investigated in 17 epithelial tumors of the ampulla of Vater by single-strand conformation polymorphism analysis and direct sequencing of DNA fragments amplified by polymerase chain reaction. The panel included 12 intestinal-type adenocarcinomas, 3 villous adenomas, 1 papillary carcinoma and 1 neuroendocrine carcinoma. Six cases (35%) contained ras mutations, affecting codon 12 of Ki-ras in 2 adenomas and 3 carcinomas, and of N-ras in 1 adenoma. All mutations were found in adenomas and among cancers with adenomatous areas, whereas none of the cases lacking adenomatous areas contained mutations. This suggested that ampullary cancers represent heterogeneous diseases with respect to the presence or absence of adenomatous areas and, among those with adenomatous areas, with respect to the presence of activated ras genes. Ki-ras mutated cases included 3 of 4 tumors which mainly involved the intraduodenal bile duct, thus suggesting that a proportion of Ki-ras-mutated ampullary cancers might correspond to those originating from the epithelium of the bile duct component of the ampulla.

“Very Well Differentiated Tubular Adenocarcinoma” of the Stomach: Its Endoscopic and Histopathological Characteristics

Between 1986 and 1991, 31 patients having tubular adenocarcinoma with low cellular and structural atypism ("very well differentiated tubular adenocarcinoma:" tub 0) underwent surgery at the National Cancer Center Hospital (NCCH). Histologically, the 31 lesions in the 31 patients were very similar to those observed in gastric adenoma (World Health Organization) with severe atypism. Their malignancy could be diagnosed only on the basis of cellular atypism, i.e., uneven distribution of chromatin in the nucleus accompanied by irregularity in the size or shape of the spindle-form nucleus, abnormal nuclear polarity and/or obvious nucleoli. Histologically, the border between the tub 0 and adenomatous areas ('front line' of carcinoma) could not be identified within the neoplastic lesion, which showed relatively regularly shaped tubuli (less structural atypism). Of the 31 cases, 30 were solitary early gastric cancer (EGC). Their clinicopathological features were compared with those of 34 cases of gastric adenoma, 237 cases of solitary well differentiated (tub 1) and 127 cases of moderately differentiated (tub 2) tubular adenocarcinoma which had been resected at the NCCH during the same period. Most (75%) of the 30 tub 0 EGCs were type IIc (depressed) macroscopically, despite their histological similarity to gastric adenoma which showed a high (90%) elevated appearance incidence. The incidence of small lesions, < 2 cm in diameter, was highest in gastric adenoma (82%), followed by tub 0 (64%), although the tub 0 lesions showed a wide range of sizes. Small lesions were less frequent in the tub 1 (43%) and tub 2 (33%) cases. The incidence of submucosal invasion was significantly lower in tub 0 cases (17%) than in tub 1 (39%) and tub 2 (46%) cases (P < 0.05). No lymph node metastasis was seen in tub 0 cases, but was seen in 6.4% and 9.4% of tub 1 and tub 2 cases, respectively. With regard to the endoscopic appearance of depressed mucosal cancer, the incidence of encroachment (moth-eaten appearance) on the tips of folds was significantly lower (10%) and the appearance of marginal elevation was significantly higher (79%) in tub 0 than in tub 1 (each P < 0.05) or tub 2 (each P < 0.01). The results suggest that 'tub 0' can be regarded as a less malignant but not benign tumor, and that its endoscopic characteristics provide valuable information which can be used to ensure that patients receive suitable treatment.

A case report of juvenile polyposis with adenomatous change and a review of 34 cases reported in Japan

It has recently come to be thought that cases of juvenile polyposis have a natural tendency to develop adenoma and/or carcinoma. Here we present a case of juvenile polyposis coli with adenomatous change in a 21-year-old male, with a review of 34 cases of juvenile polyposis in the Japanese literature, and discuss the pathogenetic development of the polyps and their malignant potential. In this case, focal or entire adenomatous areas were found in large part of the polyps in the resected sigmoid colon and rectum, though these findings had not been recognized in 23 polypectomy specimens from the rectum 10 months prior to the operation. It was suggested that adenomatous change developed quickly in a very short time.

Rat Renal Mesenchymal Tumor as an Experimental Model for Human Congenital Mesoblastic Nephroma: II. Comparative Pathology

The morphological features of kidney neoplasms induced by ethylnitrosourea (ENU) with or without prior irradiation were examined with a view to comparing them with human renal tumors of childhood. The rat renal tumors consisted of poorly differentiated, highly mitotic mesenchymal cells frequently attempting to differentiate along fibroblastic and myofibroblastic lineages. Though the host renal tubules were frequently entrapped in these tumors, immature tubules and islands of epithelial cells occasionally were seen to form an integral part of the neoplasms. Rarely, adenomatous areas surrounded by mesenchymal proliferation were observed. None of the tumors had the blastemal component that is the hallmark of nephroblastoma. The rat mesenchymal tumors resembled the human congenital mesoblastic nephroma.

Histochemical studies of intercellular components of salivary gland tumors with special reference to glycosaminoglycan, laminin and vascular elements.

In 41 salivary gland tumors, the characteristics of the intercellular components and vascular endothelial cells were surveyed by immunohistochemical staining for laminin and factor VIII-related antigen (VIII R:Ag), and by mucopolysaccharidase-digestion for glycosaminoglycan (GAG). In myxomatous areas of pleomorphic adenomas, small vessels (diameter 6.5 +/- 0.11 micron) were frequent and found to be negative or weakly positive by VIIIR:Ag staining although endothelial cells were clearly positive for VIIIR:Ag in capsule surrounding the tumor tissues. Alcian blue stainability was diminished by treatment with both Streptomyces hyaluronidase and chondroitinase. By laminin staining, a vascular pattern was clearly detected, but the majority of tumor cells were not stained. In adenomatous areas, the basement membrane-like linear laminin-staining reaction was observed to be weak and inconsistent around some tumor cell nests. However, in adenoid cystic carcinomas, laminin-positivity was much more intense than in other tumors such as pleomorphic adenoma, mucoepidermoid tumor and adenocarcinoma. In cylindromatous areas, the inner luminal surface in the pseudocysts was markedly positive for laminin, and there was weak positivity around tumor cell nests having a trabecular pattern. By immunoelectron microscopy, a juxtacellular network of replicated basal lamina of tumor cells which lined the inner surface of pseudocysts was positive for laminin. Alcian blue-positivity in the pseudocyst was abolished with heparitinase and chondroitinase, but not with hyaluronidase.

Nuclear diameter in parathyroid disease.

The nuclear diameter of chief cells was measured in 17 cases of parathyroid adenomas, four cases of secondary hyperplasia, five cases of primary hyperplasia and six cases of tertiary hyperparathyroidism. All the cases with secondary hyperplasia and tertiary hyperparathyroidism were associated with chronic renal failure. The nuclear diameter in both the adenomatous and hyperplastic areas of tertiary hyperparathyroidism were measured. The adenomatous areas of tertiary hyperparathyroidism contained nuclei of a larger diameter than those in the hyperplastic foci of the same gland. The nuclear diameter in adenomatous foci of tertiary hyperparathyroidism was similar to that in adenomas from primary hyperparathyroidism. These findings lend support to the concept of formation of autonomous adenomas against a background of reactive parathyroid hyperplasia in cases of tertiary hyperparathyroidism. Using statistical methods there were differences between the nuclear diameter in cases of primary adenomata, and cases of primary and secondary hyperplasia. Primary parathyroid hyperplasia stood out as a distinct group. The significance of these findings is discussed.

Pathogenesis of colonic polyps in multiple juvenile polyposis:Report of a case associated with gastric polyps and carcinoma of the rectum

The pathogenesis of juvenile polyps of the colon was studied in a patient with multiple juvenile polyposis who underwent proctocolectomy for rectal carcinoma and antrectomy for associated polyps of the stomach. Numerous polyps up to 3 cm in diameter were present predominantly in the cecum and rectum, and in addition there was an adenocarcinoma in the rectum. Microscopically there were five categories of lesions: 1) Hyperplastic epithelial foci and small hyperplastic polyps; 2) Typical Juvenile polyps; 3) Juvenile polyps with focal adenomatous epithelium; 4) Adenomas; and 5) and adenocarcinoma. The five categories could represent a pathogenetic sequence, beginning with epithelial hyperplasia, leading to small hyperplastic polyps which become inflamed and enlarge, forming juvenile polyps. Focal adenomatous areas which develop in some juvenile polyps might give rise to adenomas and in turn lead to carcinoma. Although juvenile polyps are generally not considered to be premalignant lesions, this case demonstrates that neoplastic changes may occur in juvenile polyps in certain individuals, and raises the possibility that these may on occasion give rise to carcinoma.

Ultrastructure of N-nitorsodibutylamine-induced tumors of the nasal cavity in the European hamster.

The ultrastructural characteristics of N-nitrosodibutylamine-induced adenocarcinomas and squamous cell carcinomas in the nasal cavities of European hamsters suggested that the cells of origin for adenocarcinomas were the goblet cells of the normal epithelial lining, whereas squamous cell carcinomas seemed to originate either from squamous metaplastic epithelium or from adenomatous areas, perhaps even as a later developmental stage of adenocarcinomas.