Tubular Tumors Research Articles

Intraductal tubular carcinoma in an adenoma of the main pancreatic duct of the pancreas head

A 50-year-old woman presented with intermittent diarrhea and upper abdominal pain. Laboratory data showed elevated serum amylase and elastase-I levels. Further image studies revealed a small, well-defined nodular lesion (8 mm in diameter) without mucin hypersecretion in the main pancreatic duct (MPD) of the pancreatic head and subsequent dilatation of the distal main pancreatic duct. A pylorus-preserving pancreatoduodenectomy with regional lymphadenectomy was performed. Microscopically, the tumor was an intraductal tubular carcinoma (ITC) in a tubular adenoma, suggesting direct histologic evidence of the adenoma-carcinoma sequence in intraductal tubular tumors, differing from previous reports of ITCs describing de novo-like development. The prognosis for ITC patients is sometimes dismal; therefore, early detection and appropriate surgical resection are mandatory to achieve long-term survival in ITC patients. MPD dilatation is a crucial sign and clue enabling the early detection of tiny pancreatic tumors.

膵管内管状腫瘍

膵管内管状腫瘍

Inhalation toxicology and carcinogenesis studies of propylene glycol mono-t-butyl ether in rats and mice.

Propylene glycol mono-t-butyl ether (PGMBE) is used as a solvent in a variety of commercial applications. Male and female F344/N rats and B6C3F(1) mice were exposed to PGMBE by whole-body inhalation for 2 or 14 weeks (0, 75, 150, 300, 600, or 1200 ppm) or 2 years (0, 75, 300, or 1200 ppm); male NBR rats were exposed for 2 weeks. The kidney and the liver were targets of PGMBE toxicity in rats. Renal lesions suggestive of alpha(2u)-globulin nephropathy were observed in male F344/N, in the 2 and 14-week studies, no kidney lesions were seen in NBR rats. In the 2-year study, male rats displayed exposure-related nonneoplastic lesions in the kidney, and may have shown marginal increases in tubular neoplasms. In the liver, the incidences of hepatocellular adenomas occurred with a positive trend in male rats, and may have been related to PGMBE exposure. In mice of both sexes, the major target of PGMBE toxicity was the liver. In the 2-week study, liver weights and in the 14-week study, liver weights and the incidences of centrilobular hypertrophy were increased. In the 2-year study, the incidences of exposure-related hepatocellular adenoma, adenoma or carcinoma combined, and hepatoblastoma occurred with a positive trend, and were significantly increased in 1200 ppm groups. In summary, exposure to PGMBE resulted in nonneoplastic lesions of the kidney characteristic of alpha(2u)-globulin nephropathy, and may have increased renal tubular neoplasms in male rats. Exposure to PGMBE also produced increases in hepatic tumors in male and female mice.

Histological and Histochemical Alterations in the Kidney Induced by Lead

Although lead intoxication is one of the most common forms of metal intoxication, the histochemical alterations in the renal tissues due to chronic lead exposure is limited and has not yet been well identified. A total of 60 male Wistar albino rats (Rattus norvegicus) were exposed to lead acetate trihydrate (0.0, 0.25, 0.5, 1.0 and 2% for 1 to 12 months) in drinking water to investigate the histological and histochemical alterations in the renal tissues due to lead. Chronic exposure to subtoxic doses of lead produced distinct progressive tubular, glomerular and interstitial damages. Tubular changes occurred earlier than glomerular and interstitial ones, and included anisokaryosis, nuclear pyknosis, karyomeglay, development of intranuclear and cytoplasmic inclusions together with tubular dilation, necrosis, vacuolization, tubular hyperplasia and solid tubular adenoma. The glomerular alterations were mainly mesangial hypercellularity, segmental proliferation, focal and segmental glomeruloscleriosis, glomerural hyalinization and glomerular tuft alterations. The findings indicate that lead produces significant histological and histochemical changes in the kidney that lead to severe complications.

Correlation of vascular endothelial growth factor expression to overall survival in feline invasive mammary carcinomas.

Samples from feline invasive mammary carcinomas (FMCs) were used to determine the prognostic significance of the immunohistochemical expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD). Forty-eight queens bearing FMCs were included in a 2-year follow-up study. Mammary tumors were classified according to the World Health Organization system and graded on the basis of histologic criteria. Tumor sections were immunostained using anti-VEGF and anti-von Willebrand factor (vWf) antibodies. VEGF expression was quantified on the basis of the percentage of positive cells. MVD of vWf-positive microvessels was determined by both mean microvessel counts and highest microvessel counts. Normal mammary gland tissues showed an inconspicuous VEGF staining. In FMCs the proportion of VEGF-positive cells was significantly higher in papillary and solid carcinomas than in tubular and papillary cystic tumors. An increased number of cells expressing VEGF was also observed in poorly differentiated FMCS. Sixteen (33.3%) of the queens bearing invasive carcinomas were still alive at the end of the 2-year follow-up period, and 32 (66.7%) had died. The VEGF expression was significantly correlated with the clinical outcome, but no correlation was observed with the invasion of lymphatic vessels. A correlation between the higher percentage of VEGF-positive cells and the unfavorable prognosis was demonstrated by the estimation of curves for overall survival (P = 0.03). Univariate analysis showed that MVD did not correlate with the overall survival. The results of our study demonstrated that VEGF expression, although not associated with increased angiogenesis, is a prognostic indicator in feline mammary tumors. In contrast, there is no support for a role of neovascularization as an indicator of survivability.

Epidemiology of neoplasia in captive black-footed ferrets (Mustela nigripes), 1986-1996.

The epidemiology of neoplastic disease was studied retrospectively in the captive population of black-footed ferrets (Mustela nigripes). Postmortem reports were reviewed and archived tissues examined from 184 of the 227 adult (>1 yr old) black-footed ferrets that died from the beginning of the current captive propagation program in late 1985 to the end of 1996. A total of 185 neoplasms, of 28 distinct phenotypes, were seen in 102 (55.4%) of these ferrets. There was more than one tumor type present in 51 ferrets. Tumors of the apocrine glands (28.3%), renal tubular neoplasms (20.7%), and biliary cystadenoma or carcinoma (20.1%) were the most common neoplasms. The probability of developing most types of neoplasms increased with age. Neoplasms of the apocrine glands were more common in males and may be hormonally influenced. The unusually high prevalence of biliary cystadenocarcinoma may be secondary to the common occurrence of intrahepatic biliary cysts in this population. Although neoplasia is an important cause of mortality in captive adult black-footed ferrets, its impact on captive propagation of the species, and on the wild population, is probably limited because clinically significant tumors are encountered almost exclusively in postreproductive ferrets (>3 yr old) and because ferrets released into their natural habitat rarely reach susceptible age.

Increased incidence of small and well-differentiated breast tumours in post-menopausal women following hormone-replacement therapy

Exposure to hormone-replacement therapy (HRT) has consistently been associated with an increased incidence of breast cancer, particularly of small tumours. Other tumour characteristics in relation to HRT have received less scientific attention. Our aim in this population-based prospective cohort study was to assess whether HRT is associated with an increased incidence of breast-cancer subgroups defined in terms of stage, type (according to the WHO system), Nottingham grade and the Nottingham Prognostic Index (NPI). Evaluation was based on a cohort of 5,865 post-menopausal women followed for an average of 9.8 years. Twenty percent of women reported current use of HRT at the time of the baseline interview. Record linkage with the Swedish Cancer Registry and local clinical registries identified 141 incident invasive breast-cancer cases. All tumours were reclassified by 1 pathologist. The incidence of breast cancer in HRT users was 377/10(5) and in non-users 221/10(5) person-years [relative risk (RR) = 1.72, 95% confidence interval (CI) 1.17-2.52]. This risk remained statistically significant after adjustment for established risk factors in a Cox proportional hazards analysis (RR = 1.66, 95% CI 1.12-2.45). Among HRT users, there was over-representation of cases with stage I tumours (adjusted RR = 2.33, 95% CI 1.44-3.76), of lobular carcinomas (RR = 4.38, 95% CI 1.60-12.0) and of tubular tumours (RR = 4.81, 95% CI 1.37-16.8). Nottingham grade I/II carcinomas (RR = 2.02, 95% CI 1.29-3.16) and cases with NPI < or = 3.4 (RR = 2.29, 95% CI 1.41-3.72) were similarly over-represented among HRT users. Incidence of breast cancer was increased in post-menopausal women who used HRT at baseline. Among HRT users, there was over-representation of tumours that, with regard to stage, type and grade, are associated with a favourable prognosis.

Cell Kinetics, p53 and bcl-2 Expression, and c-Ki-ras Mutations in Flat-Elevated Tubulovillous Adenomas and Adenocarcinomas of the Colorectum: Comparison with Polypoid Lesions

Background: Flat(-elevated) tubulovillous adenomas and adenocarcinomas of the colorectum constitute a specific type of neoplasm with superficial spreading growth. To establish their characteristics, a comparative investigation of a series of tumors was performed. Methods: A total of 56 flat tubulovillous tumors (39 adenomas, 17 invasive carcinomas) and 154 polypoid tubular or villous tumors (77 adenomas, 77 invasive carcinomas) were comparatively assessed for cell kinetics and molecular alterations. Results: Ki-67 labeling and p53 expression for both types of tumors increased along with degree of dysplasia or invasion, whereas bcl-2 expression showed an inverse decrease. However, apoptotic activity was invariably low in the flat tubulovillous tumors, as compared with the polypoid tumors, in which increase was apparent with tumor progression. The flat tubulovillous tumors also showed a higher frequency of c-Ki-ras mutations (92.9%) than the polypoid tubular tumors (40.0%). Conclusions: The flat tubulovillous tumor can be considered a distinct entity, with characteristics different from the polypoid counterpart.

Tumor induction in F344/N rats and B6C3F1 mice following inhalation exposure to ethylbenzene

Carcinogenesis studies of ethylbenzene were conducted because of its extensive use as a solvent and because it is structurally similar to the known carcinogen benzene. Groups of 50 male and 50 female Fischer rats and B6C3F1 mice were exposed to ethylbenzene by inhalation at 0, 75, 250, and 750 ppm 6 h per day, 5 days per week, for 2 years. The dose levels were selected based on the results of 13-week studies. In the 750 ppm group of male and female rats, body weights were slightly lower and incidences of renal hyperplasia and tubular neoplasms were significantly increased compared with controls. Incidence of testicular tumors was also significantly increased in male rats. Survival and body weights of the exposed groups of male and female mice and controls were comparable. Incidences of alveolar epithelium metaplasia, alveolar/bronchiolar adenoma, and hepatocyte hypertrophy and necrosis were significantly increased in the 750 ppm male mice and incidences of liver eosinophilic foci and hepatocellular neoplasms were significantly increased in the 750 ppm female mice compared with controls. Ethylbenzene is carcinogenic inducing neoplasms in kidneys and testes in Fischer rats and in lungs in male and liver in female B6C3F1 mice.

Cell proliferation in salivary gland adenocarcinomas with myoepithelial participation. A study of 78 cases.

We used three markers of cell proliferation mitotic counts, mitotic index and expression of proliferating cell nuclear antigen--to assess the proliferative activity of a series of 78 low-grade salivary adenocarcinomas with myoepithelial participation classified according to: their histological type, the predominant architectural type, and the predominant cytological type. The series included adenoid cystic carcinomas (40), epithelial-myoepithelial carcinomas (19), polymorphous low-grade adenocarcinomas (12) and basal cell adenocarcinomas (7). The proliferation indicators were found to be similar in the first three groups, being significantly lower than in the last. Tumours formed by basal cells had statistically significant higher mitotic indexes than those predominantly composed of clear cells of myoepithelial type and ductal cells. Tubular tumours, irrespective of the histological classification of the neoplasm, had proliferation indexes similar to those found in cribriform neoplasms. Solid tumours, whether formed by ductal or clear myoepithelial-type cells, had higher indexes than the neoplasms with differentiated (cribriform and tubular) patterns. The highest mean values for every proliferation indicator used were found in tumours with solid organization that were predominantly formed by basal cells. These results agree with the hypothesis that cell proliferation is inversely related to neoplastic differentiation. The identification of the prevalent cell phenotype and architecture may extend our knowledge from adenoid cystic carcinoma, whose solid variant carries a worse prognosis, and supports that the usual classification of this group of salivary adenocarcinomas would benefit to be complemented with information on tumour architecture and cellular composition.

Genetic studies of 457 breast cancers. Clinicopathologic parameters compared with genetic alterations.

Human breast cancers frequently show loss of heterozygosity (LOH) and/or amplification at specific chromosomal regions. To investigate the roles of these genetic alterations during tumor development and/or progression, 457 cases of primary breast cancer were examined for LOH at chromosomal regions 16q24, 17p13.3, and 17q21, and for amplification of the erb-B2 locus at 17q11.2 and the c-myc locus at 8q24. The genetic changes then were compared with lymph node metastasis, histologic type, and tumor stage. The LOH at 17q21 was observed more frequently in tumors of the solid, tubular type (41 of 75 [55%]) than in other types (48 of 187 [26%]) (P < 0.0001). The LOH at 17p13.3 was more frequent in scirrhous and solid, tubular tumors (77 of 141 [55%] and 48 of 88 [55%]) than in other types (29 of 89 [33%]) (P = 0.0004). Generally, mutations were seen more often in tumors with axillary lymph node metastases, undifferentiated tumors, and large or invasive tumors than in tumors considered less aggressive histopathologically. However, 22 tumors bearing three or more genetic alterations were found among 187 tumors histologically diagnosed as free of axillary lymph node metastasis; similarly, 12 of 122 t1 classification tumors and 4 of 89 histologically well differentiated tumors each contained three or more genetic alterations. Although these tumors would be regarded as having a relatively good prognosis on the basis of conventional clinicopathologic diagnosis, the authors suspect that, in fact, they do not. Patients whose tumors contain multiple genetic alterations should be treated as a new high risk group with respect to operative and/or postoperative management.

Pathology of preneoplastic and neoplastic renal tubular lesions induced in F-344 rats by sodium barbital, a nongenotoxic renal carcinogen and nephrotoxin.

Sodium barbital (NaBB), a long-duration sedative/hypnotic barbiturate, is a nongenotoxic nephrotoxin and induces chronic persistent increases in rates of cell proliferation in renal cortical tubules of male F-344/NCr rats. In 5 of our 2-stage carcinogenesis experiments with NaBB at doses of 500, 1,000, or 4,000 ppm for periods of up to 106 wk of age, renal tubular cell tumors were found in incidences of up to 25% in rats receiving only NaBB while fewer than 1% of controls had renal epithelial tumors. We reviewed renal tubular proliferative lesions found in these studies and classified the lesions based on morphology, histogenesis, and immunohistochemical findings. Renal dysplastic tubules (DTs; atypical hyperplasia), putative preneoplastic lesions rarely seen in controls, were found in the renal cortex of more than 50% of the NaBB-exposed rats. DTs were classified into grades 1-3, based on lesion size and growth patterns. All renal adenomas were usually of the basophilic phenotype, and 70% of basophilic adenomas displayed solid patterns, while tumors with papillary, cystic, or tubular patterns were seen less commonly. By serial or step sectioning of the DTs and tumors, evidence was found indicating that the high grades (grade 2 or 3) of DTs, some of which arose in the P1 or P2 segment of the proximal tubules, were sometimes connected to the adenomas. Vimentin expression was demonstrated immunohistochemically in NaBB-induced renal tubular adenomas but not in normal tubules. Tumors were usually not immunoreactive for glutathione S-transferase, placental form, but heterogeneous immunoreactivity was also seen in some tumors. Lysozyme was absent in preneoplastic and neoplastic lesions induced by NaBB, while some intact normal proximal convoluted tubules were immunoreactive. The common tumor phenotype induced by NaBB, the basophilic solid adenoma, was similar to the most common type of spontaneous renal tumor found in untreated aging F-344 rats. NaBB may promote naturally occurring renal preneoplastic or neoplastic tubular lesions of this unique phenotype, but it is also possible that it may induce these lesions de novo.

An alternative hypothesis on the role of chemically induced protein droplet (α2u-globulin) nephropathy in renal carcinogenesis

Based on associations between the accumulation of protein droplets containing α2u-globulin in proximal tubular epithelial cells and increased incidences of renal tubular neoplasms in male rats, it has been suggested that the carcinogenicity of chemicals that cause α2u-globulin nephropathy is unique to animals that synthesize this protein. Chemicals that caused α2u-globulin nephropathy and renal carcinogenicity in male rats have not been shown to produce renal tumors in animals that lack the capability for hepatic α2u-globulin systhesis, including female rats, male NBR rats, or mice of either sex. Because humans do not synthesize α2u-globulin it has been suggested that chemicals which cause renal toxicity associated with α2u-globulin accumulation do not pose an increased cancer risk to humans. In this review on the association between α2u-globulin nephropathy and renal carcinogenesis, it is apparent that (a) there are data inconsistent with the hypothesis linking these occurrences, (b) alternative mechanisms of renal toxicity and carcinogenicity are plausible, (c) data on quantitative dose-response correspondences between the various stages of α2u-globulin nephropathy and renal carcinogenicity are limited, and (d) a greater understanding of the molecular changes occurring during renal carcinogenesis is needed before assuming that the current hypothesis is correct. Future research aimed at resolving issues raised in this paper should help determine whether or not the association between α2u-globulin nephropathy and renal carcinogenesis represents a cause-and-effect relationship.

Morphometrical analysis of nuclear abnormality of tubular tumors of the stomach with image processing.

Nuclear size and shape on histological specimens were used to quantify nuclear abnormality in gastric tubular tumors. A valid technique for this morphometrical analysis by image processing was developed. Furthermore, the present study examined the nuclear size and shape to determine if they were reliable criteria to be used for differential diagnosis. Nuclear area, maximum diameter and maximum width on the histological specimens were defined as factors to represent nuclear size. Nuclear aspect ratio represented nuclear shape. Histological features revealed varied degrees of condensation of nuclei; this was due to different protocols for preparing the histological specimens. This finding indicated that the size of intermediate lymphocytes on the same specimens should be measured as a control in order to estimate the degree of nuclear condensation. The present study also demonstrated that at least 200 nuclei should be measured on the histological specimens to obtain accurate nuclear size and shape. Histologically, the nuclei in benign tubular adenoma and borderline lesions tended to be spindle‐shaped, while those in well‐differentiated type tubular adenocarcinoma tended to be round and swollen. The nuclei in borderline lesions were larger than those in benign tubular adenoma and smaller than those in well‐differentiated type tubular adenocarcinoma. Our results for the above 4 factors corresponded well with these histological findings. The nuclear size and shape on histological specimens were concluded to be reliable criteria for assessing nuclear abnormality in gastric tubular tumors and useful ones for differential diagnosis.

Morphometrical Analysis of Structural Abnormality of Tubular Tumors of the Stomach with Image Processing

Four indices, index of tubular density, index of dispersion of tubular size, degree of complexity of tubular shape and frequency of complex‐shaped tubuli, were defined to quantify the structural abnormalities of gastric tumors in morphometrical analysis by image processing. The values of each index corresponded well with the degree of each structural abnormality found pathologically. These indices were considered to be valid for representing their respective structural factors. There were significant differences among the mean values of the scores calculated by a formula using all 4 indices of benign tubular adenoma, borderline lesion and well‐differentiated type tubular adenocarcinoma (P<0.05). Therefore, the discriminant formula was considered to be valid for integrating these indices and for representing structural abnormality of gastric tubular tumors.

The human relevance of the renal tumor-inducing potential of d-limonene in male rats: Implications for risk assessment

The monoterpene d-limonene is a naturally occurring chemical which is the major component in oil of orange. Currently, d-limonene is widely used as a flavor and fragrance and is listed to be generally recognized as safe (GRAS) in food by the Food and Drug Administration (21 CFR 182.60 in the Code of Federal Regulations). Recently, however, d-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to d-limonene causes a significant incidence of renal tubular tumors exclusively in male rats. Although d-limonene is not carcinogenic in female rats or male and female mice given much higher dosages, the male rat-specific nephrocarcinogenicity of d-limonene may raise some concern regarding the safety of d-limonene for human consumption. A considerable body of scientific data has indicated that the renal toxicity of d-limonene results from the accumulation of a protein, α2u-globulin, in male rat kidney proximal tuble lysosomes. This protein is synthesized exclusively by adult male rats. Other species, including humans, synthesize proteins that share significant homology with α2u-globulin. However, none of these proteins, including the mouse equivalent of α2u-globulin, can produce this toxicity, indicating a unique specificity for α2u-globulin. With chronic exposure to d-limonene, the hyaline droplet nephropathy progresses and the kidney shows tubular cell necrosis, granular cast formation at the corticomedullary junction, and compensattor cell proliferation. Both d-limonene and cis-d-limonene-1,2-oxide (the major metabolite involved in this toxicity) are negative in in vitro mutagenicity screens. Therefore, the toxicity-related renal cell proliferation is believed to be integrally involved in the carcinogenicity of d-limonene as persistent elevations in renal cell proliferation may increase fixation of spontaneously altered DNA or serve to promote spontaneously initiated cells. The scientific data base demonstrates that the tumorigenic activity of d-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of d-limonene are (1) the male rat specificity of the nephrotoxicity and carcinogenicity; (2) the pivotal role that α2u-globulin plays in the toxicity, as evidenced by the complete lack of toxicity in other species despite the presence of structurally similar proteins; and (3) the lack of genotoxicity of both d-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation. Collectively, the evidence that the renal effects of d-limonene are confined to male rats because of the unique presence of α2u-globulin is quite compelling. In this regard, d-limonene is readily distinguished from classical renal carcinogens and should, therefore, not be subjected to traditional interspecies extrapolation and quantitative risk assessment. As d-limonene shows no toxicity or carcinogenicity in female rats or male and female mice when administered over a lifetime, it is considered safe for human consumption.

Oncocytic renal tubular adenoma(so-called oncocytoma) in seventeen-year-old girl

Renal tubular neoplasms (adenomas or adenocarcinomas) are rare in children or young adults. Herein, we report an oncocytic renal tubular adenoma (so-called oncocytoma) that was found in a seventeen-year-old girl. Preoperative evaluation included aspiration of this tumor, and we suggest that preoperative aspiration is an important procedure in the diagnosis and management of suspected renal tumors in children and young adults.

Renal tubular cell or hepatocyte hyperplasia is not associated with tumor promotion by di(2-ethylhexyl)phthalate in B6C3F1 mice after transplacental initiation with N-nitrosoethylurea

B6C3F1 mice of both sexes that had been exposed transplacentally on day 18 of gestation to 0.5 mmole N-nitrosoethylurea (NEU) were fed either normal diets or diets containing di(2-ethylhexyl)phthalate (DEHP) at 6,000 ppm beginning at 6 wk of age and continuing to 78 wk of age. At 52 and 78 wk of age, 6-26 mice from each group received a single injection of 5-bromo-2'-deoxyuridine (Brdu) at 200 mg/kg i.p. and were sacrificed 1 h later for determination of the levels of renal and hepatic DNA synthesis by the Brdu immunohistochemical technique. No differences occurred in incidences of gross or microscopic renal tubular cell tumors between the NEU (males 15%, females 21%) and NEU-DEHP groups (males 10%, females 15%) at 78 wk. The labelling index (LI) of renal cortical tubular cells was significantly increased at 78 wk (22.3 +/- 3.7/mm2 for males, 21.8 +/- 1.2 for females) in mice given NEU and DEHP as compared with NEU alone (9.7 +/- 1.0 for males, 6.9 +/- 0.7 for females). The number and sizes of focal hepatocellular proliferative lesions (FHPL), including hyperplastic foci, hepatocellular adenomas and carcinomas, were quantified by image analysis and stereology. DEHP significantly enhanced the mean volume and volume % of FHPL, including liver tumors, but not numbers of FHPL/liver. Hepatocyte LI was also not affected, at least as detected by the technique used, while FHPL had significantly increased LI (14.5-48.3) as compared with normal hepatocytes (0.5-2.4). This study provides some evidence that enhanced chronic cell replication in the kidney may not always be associated with renal carcinogenesis of tumor promotion, while tumor promotion in liver may be a consequence of increased DNA synthesis in initiated or focus cells rather than in nonproliferative parenchymal hepatocytes, which may not be target cells of some tumor promoters.

Amelioration of sodium barbital- induced nephropathy and regenerative tubular hayperplasia after a single injection of streptoxotocin does not abolish the renal tumor promoting effect of barbital sodium in male F344/NCr rats

The renal tumor promoting activity of barbital sodium (BBNa) and the role of renal tubular cell hyperplasia in tumor promotion following initiation with streptozotocin (STZ) was investigated. Six week old male F344/NCr rats were given STZ as a single i.p. injection of 50 mg/kg body wt and beginning 2 weeks later were fed diets containing 0 or 4000 p.p.m. of BBNa until they were killed at 33, 52 or 72 experimental weeks for histological evaluation and determination of levels of renal DNA synthesis by bromodeoxyuridine (Brdu) immunohistochemistry. A promoting effect on renal carcinogenesis was found by 72 weeks, but not at 33 or 52 weeks, confirming that prolonged administration of BBNa is necessary to promote renal tubular cell neoplasms. The promoting effect was evident as a higher incidence of large renal tubular tumors after 52 weeks, rather than an increase in number of dysplastic tubules, putative preneoplastic lesions. These findings suggest that the targets for the promoting activity of BBNa may be dysplastic lesions which may progress to tumors. Detailed examination by the step section technique through the entire kidneys revealed that STZ or BBNa administration induced a high incidence of putative preneoplastic renal tubular lesions (dysplasias) which seemed to be derived from the P1 or P2 segment of the nephron, also a site of high Brdu labeling index (LI) associated with BBNa toxicity. STZ administration was also associated with attenuation of BBNa-induced nephropathy and with diabetes from pancreatic islet degeneration and atrophy. The reduction in severity of nephropathy was correlated with a reduction in the LI of the renal cortical and medullary tubules, but not with the renal tumor incidence. These results indicate that decreased DNA synthesis in target cells does not eliminate tumor promoting activity in renal tubular epithelium. In addition, BBNa alone induced papillomas of the transitional epithelium of the renal pelvis and renal tubular cell adenomas.

Immunocytochemical localization of the surfactant apoprotein and Clara cell antigen in chemically induced and naturally occurring pulmonary neoplasms of mice

The localization of surfactant apoprotein (SAP) and the Clara cell antigen(s) (CCA) was studied in naturally occurring and experimentally induced pulmonary hyperplasias and neoplasms by avidin-biotin peroxidase complex (ABC) immunocytochemistry. Lungs of B6C3F1 and A strain mice with naturally occurring lesions, B6C3F1 mice given injections of N-nitrosodiethylamine (DEN), BALB/c nu/nu or nu/+ mice exposed transplacentally on Day 16 of gestation to ethylnitrosourea (ENU), or BALB/c nu/+ mice exposed to ENU at 8-12 weeks of age were preserved in formalin or Bouin's fixative. After ABC immunocytochemistry, SAP was found in the cytoplasm of normal alveolar Type II cells; in the majority of cells in focal alveolar and solid hyperplasias originating in peribronchiolar or peripheral locations; and in solid, tubular, papillary, and mixed adenomas and carcinomas. The larger mixed-pattern neoplasms and small or large tubular neoplasms usually had the least number of cells with SAP. The majority of large papillary adenomas and carcinomas in BALB/c mice exposed to ENU and in untreated A strain mice contained SAP in the nuclei of many neoplastic cells but only in the cytoplasm of a few neoplastic cells. CCA was found in normal Clara cells of bronchi and bronchioles but not in any hyperplastic or neoplastic lesion of any mouse studied. This study provided immunocytochemical evidence that the vast majority of naturally occurring and experimentally induced pulmonary neoplasms of mice are alveolar Type II cell adenomas and carcinomas.