Puberty-specific promotion of mammary tumorigenesis by a high animal fat diet.

INTRODUCTION: Increased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk. In this study, we identified the effects of peripubertal exposure to HFD and investigated its mechanism of enhancing tumorigenesis. METHODS: Three-week-old BALB/c mice fed a low-fat diet (LFD) or HFD were subjected to 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis. At 9 weeks of age, half the mice on LFD were switched to HFD (LFD-HFD group) and half the mice on HFD were switched to LFD (HFD-LFD group). Tumor gene expression was evaluated in association with diet and tumor latency. RESULTS: The peripubertal HFD reduced the latency of DMBA-induced mammary tumors and was associated with tumor characteristics similar to those in mice fed a continuous HFD. Notably, short-latency tumors in both groups shared gene expression characteristics and were more likely to have adenosquamous histology. Both HFD-LFD and continuous HFD tumors showed similar gene expression patterns and early latency. Adult switch from HFD to LFD did not reverse peripubertal HFD tumor promotion. Increased proliferation, hyperplasia, and macrophages were present in mammary glands before tumor development, implicating these as possible effectors of tumor promotion. Despite a significant interaction between pubertal diet and carcinogens in tumor promotion, peripubertal HFD by itself produced persistent macrophage recruitment to mammary glands. CONCLUSIONS: In obesity-resistant mice, peripubertal HFD is sufficient to irreversibly promote carcinogen-induced tumorigenesis. Increased macrophage recruitment is likely a contributing factor. These results underscore the importance of early life exposures to increased adult cancer risk and are consistent with findings that an HFD in normal weight premenopausal women leads to increased breast cancer risk. Notably, short-latency tumors occurring after peripubertal HFD had characteristics similar to human basal-like breast cancers that predominantly develop in younger women.

Histological subtypes of lung cancer in Chinese males from 2000 to 2012.

OBJECTIVE: To characterize the histological and epidemiological features of male lung cancer patients in China. METHODS: The demographic and histological information about male lung cancer patients identified from 2000-01-01 to 2012-12-31, was collected from the Cancer Hospital of the Chinese Academy of Medical Sciences. Relative frequencies (RF) were estimated for major histological subtypes and compared according to the years of diagnosis and birth. RESULTS: The RF of adenocarcinoma (ADC) increased from 21.96% to 43.36% and the RF of squamous cell carcinoma (SCC) decreased from 39.11% to 32.23% from 2000 to 2012 in the 15 427 male lung cancer patients included in this study (Z=17.909, P<0.0001; Z=-6.117, P<0.0001). The RF of ADC increased from 28.72% in 2000-2004, 36.88% in 2005-2008 to 48.61% in 2009-2012 in patients born after 1960. The age-adjusted RF of ADC in 2007-2012 increased consistently in all the investigated areas. CONCLUSION: The increased RF of ADC in male lung cancer patients highlights the need for further investigation of the etiologic factors of these tumors. Smoke-free policies rather than modifying tobacco products should be enforced.

The severity of duodeno-esophageal reflux influences the development of different histological types of esophageal cancer in a rat model.

The mechanism through which each histological type of carcinoma arises from the esophageal mucosa remains unknown. This study was designed to investigate whether there is an association between the severity of duodeno-esophageal reflux and the histological type of esophageal cancer. A series of 120 male Fischer rats, weighing ∼180 g, were randomized to receive one of the following procedures: duodeno-forestomach reflux (DFR) with reduced exposure to duodenal contents, duodeno-esophageal reflux (DER) with increased exposure to duodenal contents and three control operations (DFR, DER control and sham). The reflux of bile was estimated with (99m)Tc-PMT scintigraphy. All animals were fed a standard diet without carcinogen. The esophageal mucosa was assessed 50 weeks after surgery for carcinoma. The median scanned fraction rate of duodeno-esophageal reflux was significantly lower for the rodents in the DFR group than those in the DER group. Five of 28 rodents in the DFR group and 17 of the 22 rodents in the DER group developed esophageal carcinoma. None of the controls developed carcinoma. The five rodents in the DFR group developed SCC. Of 22 esophageal carcinomas for the DER group, nine were SCC, 12 ADC and one was adenosquamous carcinoma. The fraction of esophageal SCC for the DFR group was significantly higher than that for the DER group, while the fraction of esophageal ADC for the DFR group was significantly lower than that for the DER group. These observations suggest that the severity of duodeno-esophageal reflux in rodents is related to the development of different histological types of esophageal carcinoma.

What is hiding behind the pessary?

Vaginal pessaries are routinely used for initial management of pelvic organ prolapse and for women who are poor surgical candidates. Serious complications of long-term use without routine follow-up include erosion into surrounding organs and the development of fistulas. It is unclear however, if long-term use and chronic irritation could potentially contribute to development or delay the diagnosis of vaginal or cervical cancers. A 72-year-old Caucasian woman with a vaginal pessary retained for 3 years, who presented with leukocytosis and coagulopathy, was discovered to have stage II vaginal adenosquamous carcinoma upon surgical pessary removal. Chronic irritation and lack of follow-up with pessary use may contribute to masking the development and delaying the diagnosis of vaginal cancer in women with risk factors. Pessary use requires frequent follow-up to prevent complications.

High prevalence of multiple human papillomavirus infection in Japanese patients with invasive uterine cervical cancer.

OBJECTIVE: Multiple human papillomavirus (HPV) infection of the uterine cervix has been suggested as a risk factor for persistent HPV infection, resulting in the development of invasive cervical cancer. The aim of this study was to reveal the actual state of multiple HPV infection in Japanese patients with invasive cervical cancer. METHODS: Sixty fresh-frozen invasive cervical cancer tissues were examined for genotyping of HPV. The presence of HPV genotypes was determined with an HPV-DNA array, which can discriminate 25 different HPV genotypes with high sensitivity and specificity. RESULTS: Among 60 samples, 59 (96.7%) were positive for HPV. The three common genotypes were HPV-16 (83.3%), HPV-18 (45.0%) and HPV-52 (28.3%). Multiple HPV infection was observed in 47 of 60 samples (78.3%), among which 42 were infected with more than one high-risk genotype (70.0%). Multiple high-risk HPV infection was significantly more prevalent in patients below 40 years old (14/15, 93.3%) than in patients 40 years of age and over (28/45, 62.2%). CONCLUSION: The HPV-DNA array is the preferred method to detect HPV genotypes. Multiple HPV infection in Japanese patients with invasive cervical cancer seemed to be more frequent than reported in the literature.

Human papillomavirus detection and genotyping on pelvic nodes in patients with synchronous gynecological malignancies: a tool for identifying the primary site of lymphatic spread?

INTRODUCTION: Synchronous gynecological tumors are uncommon. Identifying the primary site of lymphatic spread may be difficult. METHODS: Two women with synchronous squamous cervical and adenosquamous endometrial cancers (patient A) and squamous cervical and serous borderline ovarian tumors (patient B) entered retrospectively this study. Both patients had pelvic nodal metastases of unknown origin. Uterine cervix, endometrium, and lymph nodes were tested for human papillomavirus DNA using high-sensitive polymerase chain reaction, followed by oligonucleotide microarray for genotyping. RESULTS: Human papillomavirus 16 DNA was extracted from portio vaginalis and pelvic nodes of both women. Viral homology between cervical and lymph nodal lesions helped to identify the primary metastasizing tumors in both patients. CONCLUSIONS: Human papillomavirus testing on pelvic lymphatic tissue represents a feasible tool to detect the primary site of lymphatic spread in synchronous gynecological malignancies, when uterine cervix is involved.

[Autopsy case of von Recklinghausen's disease associated with lung cancer, gastrointestinal stromal tumor of the stomach, and duodenal carcinoid tumor].

A 58-year-old man with von Recklinghausen's disease was admitted for further investigation of right chest pain. Chest X-ray revealed multiple emphysematous bullae in both lungs and a tumor shadow in the right upper lobe. Bronchofiberscopy was performed, but an adequate specimen was not obtained. The tumor was diagnosed as a non-small-cell lung cancer with direct invasion to the adjacent rib. Although chemotherapy and radiotherapy resulted in decrease in tumor size, the tumor subsequently increased in size and the patient died 14 months after the first admission. Autopsy revealed multiple emphysematous bullae, poorly differentiated adenosquamous cell carcinoma of the lung, gastrointestinal stromal tumor of the stomach, and duodenal carcinoid tumor. This case suggests the possibility that von Recklinghausen's disease associated with emphysematous bullae is a risk factor for lung cancer. It has also been suggested that the genetic abnormality responsible for von Recklinghausen's disease increases the risk for various types of malignancy. Although von Recklinghausen's disease is reportedly associated with various malignant tumors, it is quite rare for von Recklinghausen's disease to be associated with triple non-neurogenic tumors. Careful observation is mandatory for patients with von Recklinghausen's disease.

[Clinical analysis of primary lung cancer with a thin-walled cavity to explain the mechanism of thin-walled cavity formation].

We report 8 rare cases of primary lung cancer which showed a thin-walled cavity on chest X-ray and CT. We analyzed 8 cases (7 men, 1 woman) of primary lung cancer with thin-walled cavities admitted to our hospital between 1995 and 2006. The subjects were aged between 45 and 84 years of age (median: 72 years old). The reason for detection was treatment for tuberculosis in 1 case, ileus owing to metastasis to the small intestine in 1 case and tension pnumathorax 1 case, while 5 cases had abnormal chest x-ray film shadows without symptoms. Histologically, there were 5 cases of adenocarcinoma, 2 of squamous cell carcinoma, and 1 of adenosquamous cell carcinoma. Though various reports on the mechanism of the development of thin-walled cavity formation have been made, we suggest that it mainly develops by a check-valve mechanism, based on evaluation of the clinical course.

Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways.

Overexpression of hepatocyte growth factor (HGF), also called scatter factor (SF), and its receptor c-Met are associated with poor prognosis for cancer patients. In particular, breast cancer cells can produce HGF that acts in a paracrine as well as in an autocrine manner. Therefore, HGF and c-Met are putative targets for cancer therapy. To explore HGF/c-Met signaling in breast cancer, we have generated transgenic mice expressing HGF specifically in mammary epithelium under the transcriptional control of the whey acidic protein (WAP) gene promoter. WAP-HGF transgenic females developed hyperplastic ductal trees and multifocal invasive tumors after several pregnancies, some of which progressed to lung metastases. Tumors produced HGF and displayed phosphorylated c-Met, which correlated with increased Akt as well as c-myc activation. A high growth rate, as demonstrated by Ki67 nuclear antigen staining, and a lack of progesterone receptor were characteristic of the tumors. Immunohistochemical analysis revealed areas of osteopontin (Opn) expression in WAP-HGF tumors and lung metastases in agreement with a previously reported role for Opn in invasive growth. We suggest that these mice may serve as a new breast cancer model for the evaluation of the effects of unscheduled HGF expression in breast cancer.

Endometrial cancer in polyps: a clinical study of 27 cases.

PURPOSE OF INVESTIGATION: To review risk factors, clinical presentation, diagnostic methods, and histopathologic findings in 27 cases of endometrial cancer in polyps. METHODS: A descriptive, retrospective study of 204 consecutive patients with endometrial carcinoma who were diagnosed at our institution between June 1998 to June 2001. Endometrial cancer arising in polyps occurred in 27 patients (13.2%) and accounted for 1.8% of 1492 endometrial polyps diagnosed during this period. RESULTS: Patients had a mean age of 62 years. All except one woman were postmenopausal. Three breast cancer patients were currently given tamoxifen. Metrorrhagia was the presenting symptom in 74% of cases, although 22% of patients were asymptomatic at the time of diagnosis. Ultrasonography performed in 22 patients showed images compatible with an endometrial polyp in 50% of cases, myoma in 5%, and inconclusive findings in 45%. The median endometrial thickness was 11 mm (range 4-33 mm). Diagnosis was made by aspiration-biopsy in 13 patients and by hysteroscopic endometrial sampling in 13 (in one patient endometrial carcinoma was incidentally found in the surgical specimen). All patients were in FIGO Stage IA. Endometrioid carcinoma was found in 81.5% of cases. Retroperitoneal metastases were not found in 25 patients undergoing pelvic lymphadenectomy, nor neoplastic growth in the specimens of six polypeptomies performed during hysteroscopy. All patients are free of relapse after a mean follow-up of 30 months. CONCLUSIONS: Postmenopausal women with endometrial polyps diagnosed by ultrasonography should undergo directed biopsies under hysteroscopic vision. The present series confirms the good prognosis of endometrial cancer in polyps.

[Adenosquamous carcinoma of the lung (an analysis of 13 cases)]. / Akcigerin adenoskuamöz karsinomu (13 olgu nedeniyle).

Adenosquamous carcinoma of the lung is a rare disease. The biological behavior and clinicopathologic characteristics of this tumor have not been well described. In this study, we retrospectively evaluated 13 patients with adenosquamous carcinoma of the lung diagnosed at our center between January 2001 and May 2004. There were 12 males and 1 female whose ages ranged from 45 to 69 years, with a mean age of 55.9 years. Ten patients were smoker. The most frequent symptoms were chest pain and cough. Bronchoscopic examination detected that tumor was centrally located in four cases and was peripherally located in nine cases. Preoperative pathological diagnosis was squamous cell carcinoma in eight patients, non-small cell lung carcinoma in four patients and adenocarcinoma in one patient. One patient was in pathological stage IA, three patients in stage IB, one patient in stage IIA, two patients in stage IIB, five patients in stage IIIA, and one patient in stage IIIB. Twelve patients underwent resection (six, lobectomy; five, pneumonectomy; one, bilobectomy). Five of 12 patients received adjuvant therapy. Five patients died of disease within 3 and 21 months. Seven patients have had survival time between 9 and 31 months.

Pathogenetic process of lung tumors induced by inhalation exposures of rats to plutonium dioxide aerosols.

Sequential examinations were done on the pulmonary cytokinetics and pulmonary lesions in rats after inhalation exposure to (239)PuO(2) aerosols to investigate the pathogenesis of lung tumors. Total cell yields of lavaged bronchoalveolar cells as well as the estimated numbers of pulmonary alveolar macrophages were significantly reduced from 1 to 3 months after exposure but recovered thereafter to the control levels. The proportions of multinucleated or micronucleated pulmonary alveolar macrophages increased significantly in lavaged cells from 1 month, and the increase was sustained up to 18 months after exposure. Both tumor necrosis factor and nitric oxide were shown to be differentially released from stimulated cultures of pulmonary alveolar macrophages during the period from 6 to 18 months after exposure. The labeling indices of alveolar and bronchiolar epithelial cells treated with 5-bromo-2'-deoxyuridine increased significantly in lungs from 3 months and were sustained up to 18 months after exposure. Histopathological examinations revealed that after the early inflammation, hyperplasia and metaplasia of the lining of the bronchioloalveolar epithelium were predominant from 3 to 6 months, while adenomatous or adenocarcinomatous lesions appeared and developed from 12 months after exposure. The appearance of primary lung tumors, almost all of which were adenomas and adenocarcinomas, was found in the dose range of 1 to 2 Gy from 12 months after exposures. These results indicate that the pathogenetic process initiated by early cellular damage and alterations associated with inflammation is followed by the proliferative and metaplastic lesions of pulmonary epithelium, leading to the appearance and development of pulmonary neoplasms from 1 year after the inhalation exposures in rats that received a minimum lung dose of more than 1 Gy.

Endometrial cancer in premenopausal women 45 years and younger.

OBJECTIVE: To evaluate the experience with endometrial carcinoma in women 45 years or younger at the Royal Hospital for Women, Sydney, Australia. METHODS: We evaluated the clinical history, morphology, treatment, and follow-up of 17 premenopausal women 45 years or younger who had been diagnosed with endometrial cancer. All histopathology was reviewed. RESULTS: Sixteen patients received their primary treatment at the Royal Hospital for Women, and one was referred with recurrent disease. Synchronous ovarian malignancies were found in five of 17 cases (29.4%), compared with 11 of 237 (4.6%) women older than 45 (P < .001). Three other patients had secondary ovarian involvement. Five (29%) patients had stage III or IV disease. Thirteen (76.5%) women were alive with no evidence of disease 12-78 months after primary surgery; two were lost to follow-up, but had no evidence of disease at 21 and 29 months, respectively. Two women died of recurrent disease. All but two patients with stage IV disease receiving primary treatment at the Royal Hospital for Women were offered hormone replacement therapy on discharge from the hospital. CONCLUSION: Ovarian and lymph node involvement were common in women 45 years and younger with endometrial cancer. Hormone replacement therapy did not appear to compromise survival.

Clonal evolution of a radon-induced rat lung tumor.

Radon gas may represent a source of pulmonary radio-contamination either in mine or in domestic conditions. Since epidemiological studies are controversial, as long as biological markers of the exposure to such agents will not be identified, the question will remain open. We have previously shown a direct dose-dependent relationship between lung cancer occurrence and radon inhalation of rats. In this study, we report a cytogenetic study of a radon-induced rat lung tumor. Chromosome banding and chromosome specific paintings were performed on cultures of both fresh and xenografted tumors. We found by analyzing 17 sub-clones that all karyotypes presented a translocation involving rat chromosomes (RNO) 8 and 20, and a terminal deletion of RNO 15p suggesting a monoclonal origin of this tumor. RNO 15 is homologous to numerous human chromosomes (HSA), in particular to HSA 3p14.2, 3p22-p24.1 and 3p24.2-p24.3, this human chromosome being frequently lost in human lung carcinomas. Besides sharing chromosome alteration involving common features with those found in human lung cancer, this rat lung carcinoma represents a useful model to study tumor progression with respect to clonal evolution.

Lifespan studies in rats exposed to 239PuO2 aerosol. III. Survival and lung tumours.

Female, young adult, Wistar rats were given a single inhalation exposure to a submicron sized aerosol of high-fired 239PuO2 and observed during their lifespan for primary lung tumours. Rats were distributed among sham-control (n = 1052) and exposed (n = 2105) groups. Survival was significantly reduced only in rats with lung doses > 30 Gy. A total of 99 primary lung tumours were found, of which 92% were malignant and 80% were carcinomas. Of malignant lung tumours, 49 were squamous cell carcinoma, 23 adenocarcinoma, nine hemangiosarcoma, seven adenosquamous carcinoma, and three fibrosarcoma. One adenocarcinoma was found in controls and only four adenomas were seen in the exposed rat at lung doses < 1.5 Gy. The lowest doses at which lung tumours appeared in exposed rats were 1.5 Gy for squamous cell carcinoma, 3.1 Gy for adenocarcinoma. 4.1 Gy for hemangiosarcoma, and about 9 Gy for adenosquamous carcinoma and fibrosarcoma. Pulmonary squamous metaplasia was not seen in controls and was first seen in exposed rats only at lung doses > 1 Gy. Primary lung tumours were the presumed cause of death (fatal) in 60% of rats with malignant lung tumours; causes of death were equally distributed among all tumour types and doses. The incidence of all lung tumours was 0.095% in control rats, 0.21% in 1877 rats with lung doses < 1 Gy, and 41% in 228 rats with doses > 1 Gy. Lung tumour incidence increased in a linear manner from 6.9% at 2.3 Gy to an incidence of 64-88% at 16-44 Gy. Absolute malignant lung tumour risk averaged 270 lung tumours per 10(4) rat-Gy above a lung dose of 1 Gy. All types of malignant lung tumours induced by inhaled 239PuO2 exhibited a threshold at a lung dose > 1 Gy.

A primary adenosquamous carcinoma of the liver with an elevated level of serum squamous cell carcinoma related antigen.

A case of primary adenosquamous carcinoma of the liver with an elevated level of serum squamous cell carcinoma related antigen is herein reported. Various hypotheses on the pathogenesis of adenosquamous carcinoma of the liver have been set forth previously, however there is still no widely accepted theory because of the absence of any sufficient evidence. The postoperative transition of serum squamous cell carcinoma related antigen and the immunohistochemical findings using anti-involucrin antigen in this case support the hypothesis that the squamous cell carcinoma component arises as a result of the metaplastic transformation of adenocarcinoma cells.

Adenosquamous carcinoma of the colon. Case report of an unusual type.

Primary adenosquamous carcinoma of the colon is a rare entity. Its prevalent site of origin is at the level of the proximal portion of the large bowel. The tumor presents in young patients and follows a highly aggressive course. We present an extremely unusual case of adenosquamous carcinoma in which the classical mucinous and signet-ring cell adenocarcinoma was associated with the squamous component. The prognosis of this rare neoplasm is very poor.

Adenosquamous carcinoma arising in Barrett's esophagus.

Primary adenocarcinoma of the esophagus is rare in Japan and, in most cases, arises from Barrett's esophagus epithelium. A 72-year-old man reporting heartburn and dysphagia and preoperatively diagnosed with adenosquamous carcinoma arising from Barrett's esophagus underwent thoracic esophagectomy and lymph node dissection in curative resection. Pathological diagnosis of the resected specimen showed adenosquamous carcinoma (coexistent adenocarcinoma and squamous cell carcinoma) invasive to the submucosal layer; metastasis was found in regional lymph nodes. Pathological staging was pT1bN1M0, stage II. Unfortunately, the man died of liver and lung metastasis 17 months postoperatively. To our knowledge, this rare case is only the fifth reported in the English literature on adenosquamous carcinoma arising from Barrett's esophagus.

[Reflux of duodenal or gastroduodenal contents induces esophageal carcinoma in rats].

We observed the sequential development of columnar lined epithelium associated with adenocarcinoma, squamous dysplasia related with squamous cell carcinoma and adenosquamous carcinoma which were induced by duodeno-esophageal or gastro-duodeno-esophageal reflux in rats. Wistar male rats, weighing approximately 250 g were employed. Animals received total gastrectomy and were reconstructed with esophago-jejunostomy, which causes unavoidable duodeno-esophageal reflux. The animals were sacrificed every 10 weeks after surgery until 50 weeks. Erosions and basal cell hyperplasia were observed in the lower esophageal squamous epithelium at 10 weeks after surgery. At 20 weeks, glandular structures featured with galactose oxidase-Schiff-positive staining (foveolar metaplasia) appeared in the basal layer of esophageal squamous epithelium. At 30 weeks, the glands developed and formed cysts which were stained with concanavalin A (pyloric glandular metaplasia) or/and high iron diamine and alcian blue (intestinal metaplasia). Since 40 weeks after surgery, esophageal carcinomas were found. As adenocarcinomas were surrounded by the columnar-lined epithelium, squamous cell carcinoma and adenosquamous carcinoma were accompanied by squamous dysplasia. Persistent duodeno-esophageal reflux can change the stem cells of squamous epithelium to make columnar-lined cells. As part of the sequence of events leading to the development of columnar-lined epithelium, foveolar metaplasia was observed followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia. Chronic duodenal reflux induces the development of esophageal carcinoma not only adenocarcinoma also squamous cell carcinoma and adenosquamous carcinoma. These pathways of carcinogenesis were different dual patterns.