Experimental evidence for the origin of ductal-type adenocarcinoma from the islets of Langerhans

To investigate the role of the islets of Langerhans in pancreatic carcinogenesis, freshly isolated islets from male Syrian hamsters were transplanted into the right submandibular glands of 50 female hamsters that were or were not pre-treated with streptozotocin. Thyroid gland fragments, cellulose powder, and immortal hamster pancreatic ductal cells were injected into the left submandibular gland of the same hamsters. All recipient hamsters were then treated with the potent pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine weekly at a dose of 40 mg/kg of body weight for 3 weeks. Between 3 and 8 weeks later, 18 of 75 (24%) hamsters developed large ductal-type adenocarcinomas in the submandibular gland region, where islets were transplanted, but none developed tumors in the left submandibular gland. In 9 of 18 hamsters, tumors were multiple so that a total of 31 cancers were found. Eleven of these carcinomas were in the vicinity of transplanted islets, eight of which showed intra-insular ductular or cyst formation as seen in the pancreas of hamsters during pancreatic carcinogenesis. The formation of ductular structures within islets was also demonstrated in vitro. Some tumor cells in the vicinity of these islets were reactive with anti-insulin. Y chromosome message was found by polymerase chain reaction analysis in one of the three tumors examined. Also, like the induced pancreatic tumors, all three submandibular gland tumors that were examined had the mutation of the c-Ki-ras oncogene at codon 12 and all tumors expressed blood group A antigen. These and other findings strongly suggest that some components of islets, most probably stem cells, are the origin of ductal-type adenocarcinomas in this model.     

Blood group antigens in differentiated thyroid neoplasms

Alteration of cell-surface blood group antigens during malignant transformation is a well-known phenomenon that has not yet been sufficiently investigated in thyroid gland neoplasms. We evaluated 50 normal thyroid glands and 141 differentiated thyroid neoplasms (29 follicular adenomas, 30 follicular carcinomas, 56 papillary carcinomas, and 26 medullary carcinomas) both by the immunoperoxidase technique, using monoclonal antibodies against blood group antigens (A, B, H, Le(a), Le(b), Le(x), and Le(y)) and precursor substances (T, Tn, and sTn), and by affinity to the lectin from Arachis hypogea, to determine the usefulness of these antigens as tumor markers and prognostic factors. Neoplastic tissues showed immunostaining with concordant and nonconcordant expression of ABH antigens. There were statistically significant differences between normal and neoplastic tissues but not among the different neoplasms. Statistically significant differences in Lewis antigen expression were noted between normal and neoplastic tissues and between benign and malignant tumors. Tn and sTn antigen expression showed statistically significant differences between normal and neoplastic tissues. In conclusion, blood group antigens are tumor markers that are expressed more frequently in malignant than in benign neoplasms. The presence of metastases was correlated with enhanced peanut lectin receptors and a loss of A or B antigens.     

Thyroid scintigraphy in patients with thyroid tumors using 99mTc-hexakis 2-methoxy isobutyl isonitrile

Early and delayed thyroid scintigraphy with 99mTc-hexakis 2-methoxy isobutyl isonitrile (99mTc-MIBI) was performed in 18 patients with thyroid tumor, including 8 with papillary carcinoma, 1 each with follicular carcinoma, anaplastic carcinoma, and malignant lymphoma, and 7 with thyroid adenoma. Scintigrams obtained were compared with those taken with other radionuclides. In all 11 patients with malignant tumors, increased 99mTc-MIBI uptake was noted in the tumors on early images, although anaplastic carcinoma and malignant lymphoma had mild uptake. On delayed images, 99mTc-MIBI washout was noted in 45.4% (5/11). In one patient with extensive cervical lymph node metastasis, 99mTc-MIBI concentration was evident in the metastatic foci. In the 4 where, the thyroid adenoma consisted mainly of cystic degeneration, a focal defect was noted, but two of the three patients whose thyroid adenoma consisted mainly of a solid component had an intense tracer uptake in the tumors on early and delayed images. In conclusion, there were increased 99mTc-MIBI accumulations in all of the 14 solid thyroid tumors. The quality of 99mTc-MIBI scintigraphic images of thyroid tumors was equal or slightly superior to that taken with 201Tl scintigraphy. 99mTc-MIBI thyroid scintigraphy may be useful in detecting a solid thyroid tumor and its metastasis, although it cannot be used to differentiate between benign and malignant tumors.     

An unusual thyroid tumor in a child

Malignant neoplasms of the thyroid gland are quite rare in children. Winship, in his classic article, could find only 562 cases in the literature. The histopathological patterns resemble those of the adult tumors. Despite early cervical metastasis, the prognosis in general is favorable, with many long-term survivals. Prior exposure to radiation of the head and neck is a definite pre-disposing factor. Teratomas of the neck are a medical curiosity--less than 100 cases are described in the literature. The vast majority of these are found during the neonatal period, and are benign histologically. These are usually large, cystic, bulky masses which produce mechanical obstruction of the upper airway and digestive tract. Only one of these tumors, described by Pupovac in 1896, has been considered malignant. A six-year-old child was examined with a right thyroid mass of three months' duration. The thyroid scan showed a "cold nodule." At surgery, a well-encapsulated mass was found. The pathology showed a predominance of malignant spindle cells, with areas of papillary carcinoma; however, there were well-defined mucous glands present in the tumor. Clinically the child has remained well and asymptomatic. The slides have been extensively reviewed. To my knowledge no such tumor has been previously described. The tumor is considered to be a malignant thyroid tumor growing out of teratomatous tissue.     

The origins of the neural crest. Part I: embryonic induction

Nearly 500 long-term rodent carcinogenicity studies carried out by the National Cancer Institute and the National Toxicology Program were examined, and 12 chemicals were identified that produced nasal tumors: allyl glycidol ether, p-cresidine, 1,2-dibromo-3-chloropropane, 1,2-dibromoethane, 2,3-dibromo-1-propanol, dimethylvinyl chloride, 1,4-dioxane, 1,2-epoxybutane, iodinated glycerol, procarbazine, propylene oxide, and 2,6-xylidine. All 12 of these chemicals produced nasal tumors in rats, and 5 also produced nasal tumors in mice. Most of the nasal carcinogens (1) produced tumor increases in both sexes, (2) produced tumors at other sites as well, (3) had significantly reduced survival at doses that were carcinogenic, and (4) were genotoxic. Only 5 of the 12 nasal carcinogens were administered by inhalation. A variety of different types of nasal cavity tumors were produced, and specific tumor rates are given for those chemicals causing multiple tumor types. Increased incidences of nasal neoplasms were often accompanied by suppurative/acute inflammation, epithelial/focal hyperplasia and squamous metaplasia. However, high incidences of these nonneoplastic nasal lesions were also frequently seen in inhalation studies showing no evidence of nasal carcinogenicity, suggesting that in general nasal carcinogenesis is not associated with the magnitude of chronic toxicity observed at this site.     

Spindle cell malignant lymphoepithelial lesion of the parotid gland: clinical, light microscopic, ultrastructural, and in situ hybridization findings in one case

Malignant lymphoepithelial lesions (MLEL) are rare tumors of the salivary glands that show high incidence in Inuit Canadians, Alaskans, and Greenland Eskimos. The tumors are usually anaplastic or poorly differentiated squamous cell carcinomas. Focal spindle cell elements have been rarely reported. The tumors have been epidemiologically linked to Epstein-Barr virus infection. We present a case of malignant lymphoepithelial lesion showing exclusive spindle cell morphology. The patient is a 44-year-old male Inuit Canadian who presented with a long-standing history of a left parotid mass. The mass did not show evidence of rapid growth or facial nerve involvement. Parotidectomy was performed. The tumor was histologically composed of spindle cells nodules in a background of lymphocytes. The spindle cells showed no evidence of cytologic atypia but were mitotically active. Immunohistochemical staining for low-molecular-weight cytokeratin was only focally positive. The differential diagnosis included a mesenchymal neoplasm and malignant lymphoepithelial lesion. Electron microscopic examination confirmed the squamous nature of the neoplasm. Intracytoplasmic viral particles were also identified ultrastructurally. In situ hybridization for Epstein-Barr virus mRNA using a 30-base oligonucleotide probe specific for the EBER-1 gene showed very high level of expression in the tumor cells. No expression was noted in the adjacent parotid gland tissue. Our findings confirm the squamous nature of malignant lymphoepithelial lesions despite the spindle cell morphology occasionally seen in these neoplasms. They also confirm the strong role of Epstein-Barr virus infection in the pathogenesis of these tumors. This may have further diagnostic and therapeutic implications.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneous tumors and common diseases in two colonies of Syrian hamsters. I. Incidence and sites

Syrian hamsters from two colonies [Eppley colony (EC); Hannover colony (HC)] were examined for spontaneous neoplastic and noneoplastic diseases. Significant differences were found in tumor incidence (30%, EC' 42%, HC), occurrence of malignant neoplasms (15%, EC; 32%, HC), appearance of multiple primary tumors in different organs (42%, EC; 30%, HC), average survival rates of tumor-bearing animals, organ distribution and histologic types, and average survival rates of all animals. The frequencies of nonneoplastic diseases also varied between the two colonies. The findings indicated a need for precise histologic evaluation to generate information for comparative purposes regarding the use of hamsters in experimental pathology and carcinogenesis studies.     

Inhibitory effect of sarcophytol A on pancreatic carcinogenesis after initiation by N-nitrosobis(2-oxypropyl)amine in Syrian hamsters

Sarcophytol A (SaA), a cembrane-type diterpene, inhibits pancreatic carcinogenesis induced by N-nitrosobis(2-oxypropyl)amine (BOP) in hamsters. The experimental groups received two injections of BOP at 70 mg/kg dose, followed 2 weeks later by a 20 mg/kg dose injection, and were fed a basal diet or 0.01 and 0.05% SaA diets starting 1 week after the second injection of BOP. Control groups were injected with normal saline and fed the basal diet or the 0.05% SaA diet. All animals were killed 30 weeks after the start of the experiments. Seventeen BOP-treated hamsters fed the basal diet developed pancreatic tumors (77.3%) while only 12 of 21 hamsters fed the 0.01% SaA diet (57.1%) and 12 of 23 hamsters fed the 0.05% SaA diet (52.2%) developed pancreatic tumors. Pancreatic lesions included ductal hyperplasia, atypical ductal hyperplasia, and carcinoma in situ. Microscopic invasive carcinoma induced by BOP and the incidence of larger pancreatic tumors in hamsters were significantly higher in hamsters fed the basal diet than in hamsters fed the SaA diet (p < 0.05). The proliferating cell nuclear antigen (PCNA) labeling index of pancreatic carcinoma in BOP-treated hamsters fed the basal diet was 41.2 +/- 13.4%, whereas BOP-treated hamsters fed 0.01 and 0.05% SaA diets yielded PCNA indexes of 26.8 +/- 8.3 and 28.4 +/- 7.0%, respectively. k-ras mutation was detected in 40% of cancers in both groups. No pancreatic tumors developed in saline-treated groups, and no differences in body weights or histological findings in their organs, including the pancreas, were observed in either group. These findings suggest that SaA not only inhibits BOP-induced pancreatic carcinogenesis in hamsters, but also provides antipromotion and antiprogression effects on these tumors, even when SaA commences 1 week after the initiation of pancreatic carcinogenesis.     

Malignant neoplasms in cyclosporin A-induced autoimmunity (CyA-AI)

Lethally X-irradiated LEW rats reconstituted with syngeneic bone marrow and given low-dose Cyclosporine A (CyA) for 5 weeks develop, after withdrawal of CyA, symptoms of disease resembling graft-vs.-host disease (GVHD) as seen after allogeneic bone-marrow transplantation. Symptoms of disease may include acute dermatitis and chronic disease resembling scleroderma. Since anti-class II MHC cytotoxic lymphocytes are generated in this model, it has been proposed as an anti-tumor regimen in humans. We now report that LEW rats treated according to this protocol may, after cessation of CyA administration, paradoxically develop malignant neoplasms. Of 48 experimental animals, 31 developed rapidly progressive subcutaneous and/or intracutaneous tumors commencing at 6 weeks, 13 weeks and 6 months after cessation of CyA. Tumors were of mesenchymal origin, usually high-grade sarcoma, adenocarcinoma or both mesenchymal and epithelial tumors. Such tumor incidence exceeded the incidence of tumor growth in X-irradiated controls, and in rats subjected to thymectomy prior to X-irradiation and CyA administration. CyA by itself induced no tumors. Our results show that total body X-irradiation is required for tumor development but that the presence of CyA-induced autoimmune disease increases the incidence significantly.     

The dynamics of thyroid diseases in the inhabitants of Kiev and Kiev Province after the accident at the Chernobyl Atomic Electric Power Station

Autoimmune affections of the thyroid gland were found to be on the increase as were Hashimoto's disease and follicular adenoma, as evidenced by a pathomorphic study in surgically removed thyroid glands of 12684 patients over 1984-1993. Rise in the frequency of malignant tumors was moderate. Increase in the incidence of papillary microcarcinoma against the background of another surgical pathology of the thyroid gland may be an unfavourable prognostic sign of further growth of morbidity of clinically manifest forms of carcinoma in Kiev and the Kiev Province.     

Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors

The majority of familial medullary thyroid neoplasms are associated with germ-line mutations of the RET proto-oncogene, yet very little is known about the mechanisms involved in the pathogenesis of familial and sporadic nonmedullary thyroid tumors. A subset of thyroid tumors have loss of heterozygosity of chromosome 10q22-23, a region harboring the gene responsible for Cowden disease, an autosomal dominant hamartoma syndrome associated with thyroid and breast tumors. PTEN/MMAC1/TEP1 codes for a dual-specificity phosphatase and is likely a tumor suppressor gene. We sought to determine the PTEN status in a series of epithelial thyroid neoplasms. We studied 95 sporadic thyroid tumors, of which 39 were papillary thyroid carcinomas (PTCs), 12 were follicular carcinomas, 9 were anaplastic carcinomas, 5 were Hürthle cell carcinomas, 21 were nonfunctioning follicular adenomas, and 9 were Hürthle cell adenomas. Direct sequencing of PCR-amplified products was performed for all nine exons of PTEN. Two polymorphic markers, one located in intron 8 and another, a dinucleotide repeat marker, AFMa086wg9, located within intron 2, were analyzed in paired blood-tumor DNA samples to assess hemizygous deletions of PTEN. We found a somatic frameshift mutation in one PTC, which was expected to generate a premature stop codon 2 amino acids downstream. Twenty-six % of informative benign tumors (four follicular adenomas and three Hürthle cell adenomas) and only 3 of 49 (6.1%) informative malignant tumors (one PTC, one follicular carcinoma, and one anaplastic carcinoma) showed evidence of hemizygous deletion of PTEN (P = 0.046). We conclude that a subset of thyroid tumors have somatic deletions of the PTEN gene, predominantly the benign forms, and that small intragenic mutations of PTEN are infrequent in thyroid tumors. We speculate that other mechanisms of PTEN inactivation, rather than small intragenic mutations, might occur in the hemizygously deleted samples and act as the "Knudson second hit." Alternatively, other tumor suppressor genes mapping to chromosome 10q22-23 could be the actual targets for such deletions and thus represent the various hits in the pathway of multistep carcinogenesis.     

Fine needle aspiration diagnosis of malignant mixed tumor (carcinosarcoma) arising in pleomorphic adenoma of the salivary gland. A case report

BACKGROUND: True malignant mixed tumor (carcinosarcoma), composed of carcinoma and sarcoma components, is rare in salivary gland neoplasms. Even rarer is a true malignant mixed tumor arising in the pleomorphic adenoma of the salivary gland. CASE: A 64-year-old male was admitted with left pharyngeal pain. Head and neck magnetic resonance imaging revealed a left parapharyngeal mass; fine needle aspiration (FNA) cytology through the oral cavity was performed. CONCLUSION: The aspirate presented a mixture of large, pleomorphic, vacuolated, single or multinucleated cells in a mucoid matrix and clusters of adenocarcinoma cells. Additionally, occasional benign glandular cells were noted. A cytologic diagnosis of malignant mixed tumor arising in the pleomorphic adenoma of the deep lobe of the parotid gland was made and confirmed by the surgically resected specimen.     

Submandibulectomy in the treatment of pathology of the submandibular gland: our experience 1970-1995

Submandibular gland excision is proposed in the treatment of neoplastic and non neoplastic diseases; this surgical procedure can be performed by transoral or transcervical approach. The aim of the study is to demonstrate that cervical approach must be preferred because it is safer and allows a wider exposition of the surgical field. From 1970 to June 1995, 54 patients (47 with chronic sialadenitis, 7 with benign tumors and 7 with malignant tumors) were submitted to excision of the submaxillary gland. Of the 54 resections performed, 2 were completed with "functional" cervical lymphadenectomy and 1 with Radical Neck Dissection in pts. with malignant neoplasms. There were no postoperative deaths; complications occurred in 1 patient (1/54 = 1.8%) as a iatrogenic permanent lesion of the maxillary branch of the facial nerve (in detail 0/47 patients with benign disease and 1/7 (14.7%) patients with malignant disease). The cervical approach for the resection of the submaxillary gland is preferred to the transoral approach for the lower risk of iatrogenic lesions of the lingual and hypoglossal nerves and the possibility of curative resections in case of malignant neoplasms. A regulated and experimented technique through the cervical approach also lowers the risk of a lesion of the maxillary branch of the facial nerve.     

Persistence of multiple serovars of Neisseria gonorrhoeae

The nm23 gene that encodes nucleoside diphosphate (NDP) kinase has been proposed as a candidate tumor metastasis suppressor in rodent experimental carcinoma models and several types of human carcinomas. The present studies were designed to investigate, by immunohistochemical analysis, whether thyroid tissues express the nm23-H1/NDP kinase and, if so, whether the nm23-H1/NDP kinase expression is correlated to tumor metastasis suppressor potential in thyroid tumors. We found that normal thyroid epithelial cells were stained weakly but homogeneously by mouse monoclonal anti-nm23-H1/NDP kinase antibody. The staining intensity of the nm23-H1/NDP kinase in benign thyroid tumors tended to be weaker than that in normal thyroid tissues. In contrast, a series of malignant thyroid tumors expressed differently the nm23-H1/NDP kinase: the intensity of the nm23-H1/NDP kinase staining was stronger in 22 of 49 malignant tumors (45%), similar in 24 (49%), and weaker in 3 (6%) compared to that in normal tissues. The comparison of the staining intensity of the nm23-H1/NDP kinase in primary lesions of tumors with lymph node metastases and those without metastases revealed no statistically significant difference. In addition, there was also no significant difference in the nm23-H1/NDP kinase staining intensity of primary and metastatic lymph node lesions of tumors with lymph node metastases. These data indicate that the nm23-H1/NDP kinase may not be a good predictive marker for tumor regional metastatic potential in malignant thyroid tumors. We conclude that in thyroid tumors the nm23-H1/NDP kinase expression may be dissociated from metastasis suppressor activity.     

Ultrastructure of N-dibutylnitrosamine-induced tumors of the urinary bladder in European hamsters

European hamsters were treated sc with 0.025 the median lethan dose of N-dibutylnitrosamine. The induced neoplasms of the urinary bladder (transitional cell carcinomas and squamous cell carcinomas) were examined electron microscopically. Their ultrastructure indicated these tumors to be different developmental stages of the same type of tumor rather than two fundamentally different types of neoplasm.     

Neoplasms of the nasal passages and paranasal sinuses in domesticated animals as reported by 13 veterinary colleges

Three hundred cases of primary neoplasms involving the nasal cavity or paranasal sinuses were found among the reports of 12,300 microscopically confirmed neoplasms. The multispecies data were compiled from abstracts of medical records by 13 colleges of veterinary medicine in the United States and Canada from 1964 to 1973. Significant numbers of neoplasms were observed in dogs, horses, and cats. Intranasal neoplasms were more frequent than those of the paranasal sinuses in dogs and cats. Only cats had a sex difference in the occurrence of nasal neoplasms, with a male predilection. The frequency of neoplasms of the nasal cavity and paranasal sinuses increased with age in all species examined. A clear relationship could not be established between nose length and of intranasal neoplasms. Of the tumors, 80% were malignant in dogs, 68% in horses, and 91% in cats. Detailed review of medical records in a subset of 49 dogs with neoplasms of the nasal passage and paranasal sinuses revealed major clinical signs of nasal and ocular discharge, facial deformity, and stertorous breathing. Median duration of signs prior to diagnosis was 3 months and 95% of the dogs had been given treatment prior to definitive diagnosis. All 49 tumors were malignant; 27 were classified histologically as carcinomas and 22 were sarcomas. Nineteen dogs were treated, using surgery alone or in combination with radiation therapy. Median survival duration was 5 months (mean 6.7 mo).     

Effects of grafts of single anterior pituitary glands on the incidence and type of mammary neoplasm in neutron- or gamma-irradiated Fischer female rats

Three batches comprised of 48 young adult Fischer female rats each were subjected to total-body irradiation with 50 rads modified fission neutrons, or were given 600 rads 137Cs gamma-rays, or served as unirradiated controls. On the day following exposure, one-half of each batch was grafted with a single anterior pituitary gland beneath the left kidney capsule. The animals were observed for mammary neoplasia and all those that died during the experiment were autopsied. The experiment was terminated 538 +/- 13 days after irradiation when all neutron-irradiated, pituitary-grafted animals had one or more mammary tumors. Only 2 of the 23 untreated rats that survived until termination of the experiment developed mammary fibroadenomas, and none had mammary carcinomas. The incidence of fibroadenomas was increased, and a single carcinoma was found, in unirradiated rats with pituitary grafts. Irradiation alone caused an increase in the incidence of mammary fibroadenomas and the appearance of carcinomas. Fibroadenomas were markedly increased by the addition of pituitary grafts to irradiation. Carcinoma incidence was less markedly affected. The neutron dose of 50 rads was slightly more effective in inducing mammary neoplasms than the 600-rad dose of gamma-rays.     

Solitary fibrous tumour of the tongue

In a review of pulmonary tumors diagnosed at our institute from 1976 to 1995, we found 20 malignant and 12 benign rare tumors, which accounted for 0.57 and 0.34% of all pulmonary tumors, respectively. The histological types of these rare malignant tumors were malignant lymphoma (6/20), carcinosarcoma (3/20), mucoepidermoid carcinoma (2/20), bronchial gland mixed tumor (2/20), adenocystic carcinoma (1/20), myoepithelioma (1/20), leiomyosarcoma (1/20), epitheloid hemangioendothelioma (1/20), hemangiopericytoma (1/20), malignant melanoma (1/20) and choriocarcinoma (1/20). Benign rare tumors involved papilloma (3/12), lipoma (3/12), leiomyoma (3/12), adenoma (1/12), fibroma (1/12), and meningioma (1/12). The clinical and pathological features of malignant tumors were roughly the same as those of common pulmonary carcinomas. In contrast, benign tumors were never larger than 3 cm and were more commonly located in the central parts of the lung, which explained the relatively frequent symptoms of wheezing and fever associated with obstructive pneumonia.     

Missed opportunities for prevention: smoking cessation counseling and the competing demands of practice

Activating mutations in and expression of the Ha-ras gene were examined in benign and malignant female Sprague-Dawley rat mammary gland tumors induced by the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by a diet high in polyunsaturated fat. Ha-ras mutations were detected in codons 12 and 13 by selective polymerase chain reaction amplification of mutated sequences and nucleotide sequencing. The percentage of Ha-ras mutations in carcinomas from PhIP-treated rats was significantly higher in rats on a low-fat diet than in rats on a high-fat diet (82% (nine of 11) vs 26% (seven of 27), respectively, P < 0.01). In addition, whereas 56% of the carcinomas with Ha-ras mutations from rats on a low-fat diet carried double Ha-ras mutations, none of the carcinomas from rats on a high-fat diet had double mutations. Ha-ras mutations were also detected in benign tumors (largely adenomas) induced by PhIP in rats on different diets; two of eight and three of four benign tumors examined from rats on low-fat and high-fat diets, respectively, had Ha-ras mutations, suggesting that activating Ha-ras mutations alone are not sufficient for PhIP-induced tumors to become malignant. No differences were observed in the level of Ha-ras mRNA expression in the different groups. In our animal model, a high-fat diet increased the incidence and percentage of malignant PhIP-induced mammary gland tumors yet decreased the percentage of carcinomas showing Ha-ras mutations. Thus, the complement of genetic alterations associated with PhIP-induced mammary gland carcinogenesis is probably altered by the level of dietary fat.