GLUT-1 Expression in Proliferative Endometrium, Endometrial Hyperplasia, Endometrial Adenocarcinoma and the Relationship Between GLUT-1 Expression and Prognostic Parameters in Endometrial Adenocarcinoma.

OBJECTIVE: Malignant cells show increased glucose uptake in in vitro and in vivo studies. This uptake is mediated by glucose transporter proteins. GLUT-1 is the most common transporter protein, and its expression is reported to be increase in many human cancers. The aim of this study is to determine the GLUT-1 overexpression in benign, hyperplastic, and malignant endometrial tissues, to evaluate the usefulness of GLUT-1 expression in endometrial hyperplasia, and to determine its role in the neoplastic progression to endometrioid type adenocarcinoma. We also aimed to analyze prognostic clinical parameters, predict prognosis, and survival. MATERIAL AND METHOD: We examined immunohistochemical expression of GLUT-1 in 91 cases of endometrial hyperplasia, 100 cases of endometrioid type adenocarcinoma, and 10 proliferative endometrial tissues. The percentage of positive cells and staining intensity were assessed in a semi quantitative fashion and scored (1+ to 3+). RESULTS: GLUT-1 immunoreactivity was not present in proliferative endometrium. Twenty-nine (31.9%) of 91 endometrial hyperplasia cases showed positive immunoreactivity, of which only six were cases of hyperplasia without atypia while 23 of them were cases with atypia. We found GLUT-1 positivity of 95% in endometrioid type adenocarcinoma. GLUT-1 overexpression was not significantly correlated with any of the clinicopathological parameters except histological grade in endometrioid adenocarcinoma; the survival was not found to be correlated with GLUT-1 expression. CONCLUSION: GLUT-1 immunostaining may be useful in distinguishing hyperplasia without atypia from hyperplasia with atypia; GLUT-1 overexpression is a consistent feature of endometrioid adenocarcinoma. A correlation between GLUT -1 expression and tumor grade has been found, although other prognostic parameters and survival has no meaningful correlation.

Asfixia por papilomatosis respiratoria recurrente / Asphyxiation due to recurrent respiratory papillomatosis

La asfixia causada por factores intrínsecos de las vías aéreas, tales como los tumores de la laringe, es poco frecuente. Presentamos un caso de muerte súbita en una niña de 10 años de edad, que falleció durante un episodio agudo de dificultad respiratoria severa. La autopsia médico-legal reveló la presencia de una masa endolaríngea diagnosticada como papilomatosis respiratoria recurrente (PRR). La PRR es una rara enfermedad causada por el virus del papiloma humano (VPH) que se transmite por vía vertical de una madre con infección ano-genital activa o latente. El tumor puede aumentar de tamaño y potencialmente bloquear la luz de la laringe provocando asfixia. El uso de medios de fijación no formólica, con resultados análogos a los esperados con formol, permitieron la extracción de ADN viral del tumor (AU)

Asphyxiation due to intrinsic factors such as tumors of the larynx is uncommon. Here, we report a case of sudden death in a 10 year-old girl who died after an acute episode of severe dyspnea. The medico-legal autopsy revealed the presence of an endolaryngeal mass diagnosed as Recurrent respiratory papillomatosis (RRP). RRP is a rare benign tumor caused by Human papilloma virus (HPV) vertically transmitted from a mother with latent or active ano-genital infection. The tumor may grow and block the laryngeal inlet causing asphyxiation. No formaldehyde was used for fixation, a different product with similar results, allowed the extraction of viral DNA from the tumor (AU)

Epitheliocystis in lake trout Salvelinus namaycush (Walbaum) is associated with a ß-proteobacteria.

Lake trout Salvelinus namaycush (Walbaum) raised for stocking experienced yearly (2011-13) winter epizootics of epitheliocystis. Affected fish were dispersed on the bottom of the tank, had decreased feed and fright response, and mortality often reached 40%. Peak mortality occurred within 3 weeks of the appearance of clinical signs, and outbreaks typically lasted 6 weeks. Affected fish had no gross lesions but histologically had branchial epithelial necrosis and lamellar hyperplasia, with small to large numbers of scattered epithelial cells containing 10- to 20-µm inclusions. A longitudinal study was undertaken of one annual outbreak, and lamellar hyperplasia was most closely associated with mortality. The number of inclusions was statistically greater (P < 0.05) before and during peak mortality, but inclusions were present in low numbers before clinical signs occurred. Results of histochemical staining, immunohistochemistry and transmission electron microscopy supported the presence of a ß-proteobacteria rather than a Chlamydiales bacterium within inclusions. PCR primers to identify Chlamydiales did not give consistent results. However, the use of universal 16S rDNA bacterial primers in conjunction with laser capture microdissection of inclusions demonstrated that a ß-proteobacteria was consistently associated with affected gills and is more likely the cause of the disease in lake trout.

Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma.

In carcinogenesis of peripheral pulmonary carcinomas, multiple genetic and epigenetic alterations are involved. In this study, we quantified methylation levels of repetitive DNA elements (L1 and Alu) and six CpG island methylator phenotype (CIMP)-panel markers in various lesions representing steps in the development of lung adenocarcinoma (ADC), including atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive ADC. We then assessed methylation levels in an independent set of stage I ADCs (n = 100) and correlated methylation status with clinicopathological findings and clinical outcome. The pattern of changes in the methylation levels of L1 and Alu was different during progression of the lesion along the process of multistep carcinogenesis. A methylation level of >52.4 % of L1 and of >19.7 % of Alu in stage I ADC was associated with shorter cancer-specific survival in univariate but not in multivariate analysis. A tumor to normal lung tissue methylation ratio of >0.693 of L1 was an independent parameter heralding poor prognosis for stage I ADC patients. Methylation of CIMP-related genes was found in ADC. Stage I ADC cases without methylation of any of the six markers had a significantly shorter cancer-specific survival than ADC with methylation of one or more markers. The combination of tumor to normal L1 methylation ratio > 0.693 and absence of methylation of CIMP markers correlated independently with shorter cancer-specific survival. In conclusion, our findings suggest that Alu hypomethylation is an early and L1 hypomethylation a later event during multistep pulmonary carcinogenesis. The prognostic significance of the combination of methylation status of L1 and CIMP markers must be validated in large-scale studies of pulmonary ADC.

An outbreak of thyroid hyperplasia (goiter) with high mortality in budgerigars (Melopsittacus undulatus).

An outbreak of goiter with high morbidity and mortality in a flock of budgerigars (Melopsittacus undulatus) in California is described. Forty-five out of 400 adult birds exhibited signs of illness, weight loss, and enlargement in the crop area; 15 of the 45 birds died over a 2-3-month period. Diet consisted of a commercial mixture with the addition of broccoli, whole oats, and carrots, but no minerals or supplements. Six budgerigars were subjected to necropsy; all 6 birds had severely enlarged thyroid glands. Thyroid follicular hyperplasia was histologically observed in all birds examined, while granulomatous thyroiditis and microfollicular adenoma were observed in 2 birds, respectively. Virological, bacteriological, parasitological, and heavy metal analyses were negative or within normal limits. The total iodine in the thyroid glands of affected birds was measured by inductively coupled plasma-mass spectrometry. Following iodine supplementation and removal of broccoli from the diet, the owner reported weight gain and a reduced death rate among clinically affected birds; no additional birds became sick. The presence of broccoli with its iodine-binding ability and the complete lack of added minerals in the diet of these animals were thought to be the predisposing factors for the outbreak in the present study. Outbreaks of goiter accompanied by high mortality are rare in any species and, to the best of the authors' knowledge, have not been described previously in any avian species. Recognition of this condition may help improve medical, welfare, and trade standards concerning this species.

Association of small foci of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with adenocarcinoma of the lung.

DIPNECH is regarded as a precursor lesion of neuroendocrine lung tumors, specifically carcinoids. A relationship with lung adenocarcinomas has not been clearly established so far. We present a series of four cases with a concomitant presence of adenocarcinoma and DIPNECH in the lung. The cases were retrieved from the archives of the Institutes of Pathology of the Jena University Hospital and the Charité, Berlin. The clinical data were collected from the hospital information system. The microscopic findings of adenocarcinoma and DIPNECH were reviewed. A panel of neuroendocrine and epithelial markers was analyzed immunohistochemically. In addition, the H&E slides of a series of 82 lung carcinomas were reevaluated for the presence of DIPNECH foci and the parameters of the IASLC/ATS/ERS classification for lung adenocarcinoma. DIPNECH foci were composed of small intramucosal nests of proliferating pulmonary neuroendocrine cells alongside or at the periphery of terminal airways. All detected foci measured less than 5mm in maximal diameter and showed a consistent reactivity against Synaptophysin. They did not express epithelial markers of squamous cell carcinoma and adenocarcinoma. In three cases, the DIPNECH foci were clearly associated with the adenocarcinoma, while in one case, they were observed in the non-neoplastic lung tissue. The adenocarcinoma with DIPNECH inside mainly showed low grade histology, while the fourth case was intermediate to high grade. The histologic evaluation of the HE slides of the other 82 lung cancer cases showed no suspected or definite DIPNECH foci. Within this series, we could confirm the prognostic significance of the IASLC/ATS/ERS classification of lung adenocarcinoma. Our series suggest that a subset of lung adenocarcinoma is characterized by the concomitant presence of DIPNECH within the tumor, suggesting a causal relationship. These adenocarcinomas seem to be low grade ones, and may have a particular tumorigenesis and clinical behavior. These observations need to be confirmed in larger tumor collectives. We could confirm the prognostic relevance of the new adenocarcinoma classification.

Blurry boundaries: do epithelial borderline lesions of the breast and ductal carcinoma in situ have similar rates of subsequent invasive cancer?

BACKGROUND: The histology of epithelial "borderline lesions" of the breast, which have features in between atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), is well described, but the clinical behavior is not. This study reports subsequent ipsilateral breast events (IBE) in patients with borderline lesions compared with those with DCIS. METHODS: Patients undergoing breast-conserving surgery for borderline lesions or DCIS from 1997 to 2010 were identified from a prospective database. IBE was defined as the diagnosis of subsequent ipsilateral DCIS or invasive ductal carcinoma. RESULTS: A total of 143 borderline-lesion patients and 2,328 DCIS patients were identified. Median follow-up was 2.9 and 4.4 years, respectively. 7 borderline-lesion and 172 DCIS patients experienced an IBE. 5 year IBE rates were 7.7 % for borderline lesions and 7.2 % for DCIS (p = .80). 5 year invasive IBE rates were 6.5 and 2.8 %, respectively (p = .25). Similarly, when analyses were restricted to patients who did not receive radiotherapy, or endocrine therapy, or both, borderline-lesion and DCIS patients did not demonstrate statistically significant differences in rates of IBE or invasive IBE. CONCLUSIONS: When compared with DCIS, borderline lesions do not demonstrate lower rates of IBE or invasive IBE. Despite "borderline" histology, a 5 year IBE rate of 7.7 % and an invasive IBE rate of 6.5 % suggest that the risk of future carcinoma is significant and similar to that of DCIS.

Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres (pattern 1) shows superior survival to patterns 2 and 3: a meta-analysis of 56 cases.

AIMS: Angioimmunoblastic T-cell lymphoma (AITL) may present in patterns 1, 2 or 3, representing those with hyperplastic, regressed or effaced germinal centres (GCs), respectively, but the prognostic utility of this subclassification has not been previously validated. METHODS AND RESULTS: Twenty-five cases of AITL were reviewed immunohistologically and with in-situ hybridization for Epstein-Barr virus-encoded RNA and polymerase chain reaction for T-cell receptor gamma and immunoglobulin heavy chain clonality and followed for up to 120 months. Four cases had conventional hyperplastic GCs, two had floral GCs, and one had progressively transformed GCs, consistent with pattern 1 and one additional case had hyalinized GCs, consistent with pattern 2. The remaining 17 (pattern 3) cases lacked morphologically discernible GCs. The Kaplan-Meier survival distribution of pattern 1 cases (5-year survival 83%) was superior to that of pattern 2 and 3 cases [5-year-survival 36% (P = 0.0417)] only when combined with the 31 cases, seven of which were pattern 1, that Attygalle et al. had followed for up to 247 months and previously published. Furthermore, the development of B-lineage (classical Hodgkin or diffuse large-cell) lymphoma was associated exclusively with pattern 3 (P = 0.0057). CONCLUSIONS: Pattern 1 represents an indolent phase/grade of AITL, unassociated with the development of secondary B-lineage lymphoma and uninfluenced by treatment regimen.

Role of cyclooxygenase-2 in tumor progression and survival of head and neck squamous cell carcinoma.

Inhibition of cyclooxygenase-2 (COX-2) pathways may have significant implications for the prevention and treatment of head and neck squamous cell carcinoma (HNSCC). COX-2 is overexpressed in both premalignant lesions and invasive HNSCC. We examined COX-2 expression by immunohistochemistry in normal tissues, different stages of premalignant lesions, and carcinoma in situ (CIS). We also evaluated the correlation between COX-2 expression and clinical characteristics of HNSCC patients. Tissue specimens were obtained from the following: premalignant lesions from 25 subjects enrolled in a biochemoprevention trial, tumor samples collected at diagnosis from 38 HNSCC patients enrolled in an induction chemotherapy trial, and normal control tissues from 10 noncancer, nonsmoking subjects. COX-2 was expressed in early and intermediate stages of premalignant lesions, increasing first in the basal and parabasal layers, then lower spinous, and upper spinous layers. This correlation was noted in normal epithelium (P < 0.0001), histologically normal in-field samples (P < 0.0001), low-grade dysplasia (P = 0.024), and moderate-grade dysplasia (P = 0.009), but was lost in the majority of high-grade dysplasia/CIS (P = 0.896). COX-2 expression was also noted to increase progressively through the early stages of premalignancy, and to decrease in severe/CIS stage and invasive carcinoma. COX-2 expression in tumors from patients treated with induction chemotherapy was correlated with overall survival after controlling for clinical variables. These findings elucidate the differential expression pattern of COX-2 in stages of head and neck premalignant lesions and invasive carcinoma, supporting the rationale for COX-2 inhibition as an important strategy for cancer chemoprevention. Further validation of COX-2 expression is needed in prospective ongoing chemoprevention trials.

Hyperplastic goitre and mortality in captive-reared black stilts ( Himantopus novaezelandiae ).

AIM: To study the gross, histopathological and clinico-pathological findings in cases of hyperplastic goitre in sub-adult captive- reared black stilts following their release on riverbeds in the south Canterbury region of New Zealand. METHODS: Necropsies were undertaken on the recovered carcasses of 48 black stilts over a 3-year period (1997-1999). The cause of death was determined, and thyroid glands were examined histopathologically and compared with those of free-living pied stilts. Concentrations of triiodothyronine (T3) and thyroxine (T4) in the serum of sub-adult and adult stilts were measured before and after iodine supplementation. RESULTS: The main causes of death of captive-reared black stilts following release were trauma, predation and starvation. An increase in size of the thyroid gland due to follicular hyperplasia and dilation was seen in all birds with intact thyroid glands (n=27). Dysplastic follicular changes such as epithelial desquamation, lipid deposition and haemorrhage were common in a large proportion of individuals with goitre. Dietary supplementation with iodine greatly improved survival rates in sub-adults following release, and significantly increased concentrations of T3 and T4 in serum. CONCLUSIONS: Subclinical goitre due to thyroid hyperplasia and dysplasia was the cause of hypothyroidism and this contributed to the poor survival of released sub-adult black stilts raised in captivity. Iodine supplementation of the diet of captive adults and sub-adults resulted in increased concentrations of T3 and T4 in serum and improved survivability.

Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia.

Coronary artery disease, leading to myocardial infarction and ischaemia, affects millions of persons and is one of the leading causes of morbidity and mortality worldwide. Invasive techniques such as coronary artery bypass grafting are used to alleviate the sequelae of arterial occlusion. Unfortunately, restenosis or occlusion of the grafted conduit occurs over a time frame of months to years with a gradual reduction in patency, especially in vein grafts. The events leading to intimal hyperplasia (IH) formation involve numerous cellular and molecular components. Various cellular elements of the vessel wall are involved as are leucocyte-endothelial interactions that trigger the coagulation cascade leading to localized thrombus formation. Subsequent phenotypic modification of the medial smooth muscle cells and their intimal migration is the basis of the lesion formation that is thought to be propagated by an immune-mediated reaction. Despite intense scrutiny, the pathophysiology of IH remains an enigma. Although several growth factors, cytokines and numerous other biomolecules have been implicated and their relationship to prohyperplasia pathways such as the phosphatidyl-inositol 3-kinase (PI3K)-Akt pathway has been established, many pieces of the puzzle are still missing. An in-depth understanding of early vein graft adaptation and progression is necessary to improve the long-term prognosis and develop more effective therapeutic measures. In this review, we have critically evaluated and summarized the literature to elucidate and interlink the numerous established and emerging factors that play a key role in the development of IH leading to vein graft restenosis.

Primary hyperparathyroidism and heart disease--a review.

Primary hyperparathyroidism (pHPT), caused by solitary parathyroid adenomas in 85% of cases and diffuse hyperplasia in most of the remaining cases, overproduces parathyroid hormone (PTH), which mobilizes calcium to the blood stream. Renal stones, osteoporosis and diffuse symptoms of hypercalcaemia, such as constipation, fatigue and weakness are well-known complications. However, in Western Europe and North America, patients with pHPT are nowadays usually discovered during an early, asymptomatic phase of the disease. It has been reported that patients suffering from symptomatic pHPT have increased mortality, mainly due to an overrepresentation of cardiovascular death. pHPT is reported to be associated with hypertension, disturbances in the renin-angiotensin-aldosterone system, and structural and functional alterations in the vascular wall. Recently, studies have indicated an association between pHPT and heart disease, and studies in vitro have produced a number of theoretical approaches. An increased prevalence of cardiac structural abnormalities such as left ventricular hypertrophy (LVH) and valvular and myocardial calcification has been observed. Associations have been found between PTH and LVH, and between LVH and serum calcium. LV systolic function does not seem to be affected in patients with pHPT, whereas any influence on LV diastolic performance needs further evaluation. The aim of this review is to clarify the connection between pHPT and cardiac disease.

Vascular endothelial growth factor (VEGF)-eluting stents: in vivo effects on thrombosis, endothelialization and intimal hyperplasia.

Local drug delivery by stent can reduce in-stent restenosis. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen. After stenting, the arterial wall is almost denuded of endothelium. This loss of endothelium contributes to the smooth muscle cell (SMC) proliferation seen in restenosis, since the endothelium actively inhibits SMC hyperplasia. Over time, the endothelium recovers and SMC hyperplasia is arrested. The capacity of VEGF-coated stents to accelerate re-endothelialization, and to therefore reduce restenosis and thrombosis, was tested in this study. Radiolabeled VEGF was absorbed onto stents and released over nine days in an in vitro perfusion circuit. VEGF-coated stents were deployed in arterial segments to study local tissue release. A New Zealand White rabbit iliac artery model for stent implantation was used. Re-endothelialization and thrombosis were assessed after seven days. Further animals were examined 28 days post-procedure for in-stent restenosis. Stented vessels were resin-embedded, sectioned and stained. Intimal thickening was calculated using computerized morphometry. In vitro, the stents released 80% of the initial load over nine days. At seven days, thrombus was significantly reduced (12.5 mg for controls versus 0 mg for VEGF; p = 0.014). No beneficial effect was seen on endothelialization, nor on intimal hyperplasia. Neointimal area was 2.2 0.9 mm2 for controls versus 2.4 1.8 mm2 for VEGF (p = 0.8). These VEGF-eluting stents do not accelerate re-endothelialization or inhibit restenosis. Stent thrombosis appears to be reduced, which may make these stents less thrombogenic and be valuable in higher-risk cases.

Topical application of beta-radiation to reduce intimal hyperplasia after carotid artery balloon injury in rabbit. A possible application for brachytherapy in vascular surgery.

PURPOSE: Endovascular brachytherapy for the prevention of intimal hyperplasia (IH) and restenosis after balloon/stent angioplasty has proven effective both in animal preparations and clinical trials. A variety of beta-emitting isotopes and catheter-based devices have been developed for the delivery of low-dose radiation in clinical coronary and peripheral trials. No platform, however, has yet been developed for brachytherapy in concert with vascular surgical operations. The purpose of this study was to evaluate the vascular histopathologic response following balloon injury to rabbit carotid arteries with and without topically applied low-dose beta-radiation. METHODS: The beta-emitting isotope strontium-90 (Sr-90) was conjugated onto the matrix of polypropylene (PLYP) mesh. Rabbit carotid arteries were balloon-injured with a #2 embolectomy catheter. Six carotid arteries were wrapped with nonradioactive PLYP mesh (controls) and Sr-90 ( approximately 90 microCi) PLYP mesh in order to deliver low-dose radiation to the vessel wall from the external (adventitial) surface. Tissue was harvested at 6 weeks and processed for histologic examination. RESULTS: There was consistent blockade of fibrocellular neointima formation with virtually no neointima present in all treated segments, compared to moderate neointima formation in controls. Medial thinning and smooth muscle cell (SMC) necrosis were also associated with topical brachytherapy. CONCLUSION: beta-Radiation applied by an externally wrapped PLYP mesh labeled with Sr-90 markedly suppressed neointima formation in an animal vascular surgical injury model. Further studies, however, are necessary to determine a suitable isotope and dosage for clinical application.

Apoptotic index: use in predicting recurrence in breast cancer patients.

Apoptosis maintains tissue homeostasis through its ability to control cell population and has been extensively studied in human cancers. Relation of apoptosis to prognosis is still controversial. In this study, we analyzed the prognostic significance of apoptotic and mitotic indices (AI & MI) using hematoxylin and eosin stained slides by light microscopy in breast cancer patients. In our study, apoptotic index was significantly associated with predicting relapse free survival (RFS), distant recurrence free survival (DRFS) and overall survival (OS) with lesions having higher apoptotic index showing poor prognosis. Our results also point out that quantitation of apoptotic index by simple light microscopy as a routine practice along with histological diagnosis, could provide additional prognostic information in patients who are at high risk of developing recurrence with breast cancers.

Effects of in vivo heregulin beta1 treatment in wild-type and ErbB gene-targeted mice depend on receptor levels and pregnancy.

Mice heterozygous (+/-) for either heregulin (HRG), ErbB2, or ErbB3 were created by gene targeting, resulting in the loss of one functional gene copy and an associated decrease in targeted protein. We examined the in vivo activity of recombinant HRG peptide, rHRG beta1 (amino acids 177 to 241), in the three heterozygous mouse lines and in wild-type (WT) mice, both pregnant and nonpregnant. Nonpregnant WT and HRG(+/-) mice of both sexes were sensitive to rHRG beta1 treatment as evidenced by a high mortality rate associated with abdominal enlargement and parietal cell loss. However, pregnant WT mice and ErbB2 and ErbB3 heterozygous mice treated with rHRG beta1 were less affected, with significantly lower mortality rates and a less severe abdominal phenotype. Histological analysis revealed extensive breast ductal hyperplasia in females of all genotypes after rHRG beta1 treatment. Hyperplasia of other epithelial tissues such as the pancreas and intestine and the growth of cardiac nerve bundles were also observed, independent of sex.

The association between atypical adenomatous hyperplasia and primary lung cancer.

Atypical adenomatous hyperplasia (AAH) has been suggested as the adenoma in an adenoma-carcinoma sequence in the lung periphery. From 1989-1998, we undertook a systematic, prospective search for AAH in lungs resected for cancer. AAH was found in 67 of 554 patients (12. 1%) with primary lung carcinoma (9.2% in male patients and 19.0% in females). AAH was found in lungs bearing adenocarcinoma (23.2%) more frequently than with large cell undifferentiated carcinoma (12.5%) or squamous carcinoma (3.3%). A greater percentage of females with adenocarcinoma had AAH (30.2%) than did males with adenocarcinoma (18.8%). Numbers of AAH ranged from 1-42 per patient and more patients had small numbers of AAH, although 12 patients had 6 or more AAH foci. Larger numbers of AAH tended to be found in adenocarcinoma-bearing lungs. Ten of the 67 patients with AAH and primary lung carcinoma (15%) had multiple primary cancers (range 2-6), all of which were adenocarcinoma. Synchronous cancers were rare in lung tumour-bearing resections without AAH. Patients with AAH show no difference in post-operative survival to those without, for all stages of carcinoma and for Stage I disease alone. This study provides evidence for a strong association between atypical adenomatous hyperplasia and primary lung adenocarcinoma and lends weight to the AAH/adenoma-carcinoma hypothesis.

Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver.

Studies with tumor necrosis factor p55 receptor- and interleukin-6 (IL-6)-deficient mice have shown that IL-6 is required for hepatocyte proliferation and reconstitution of the liver mass after partial hepatectomy. The biological activities of IL-6 are potentiated when this cytokine binds soluble forms of its specific receptor subunit (sIL-6R) and the resulting complex interacts with the transmembrane signaling chain gp130. We show here that double transgenic mice expressing high levels of both human IL-6 and sIL-6R under the control of liver-specific promoters spontaneously develop nodules of hepatocellular hyperplasia around periportal spaces and present signs of sustained hepatocyte proliferation. The resulting picture is identical to that of human nodular regenerative hyperplasia, a condition frequently associated with immunological and myeloproliferative disorders. In high expressors, hyperplastic lesions progress with time into discrete liver adenomas. These data strongly suggest that the IL-6/sIL-6R complex is both a primary stimulus to hepatocyte proliferation and a pathogenic factor of hepatocellular transformation.

Intraductal neoplasms of the pancreas.

BACKGROUND: Since 1980 a group of pancreatic tumors have been termed intraductal papillary mucinous tumors (IPMT). Because these tumors occupy an intraductal position they are demonstrated by pancreatography to reside in the main pancreatic duct (MPD) or side branch ducts (SBD). Lesions of IPMT result in abdominal pain or pancreatitis symptoms because mucin production or papillary growth results in ductal obstruction. Only 104 cases had been reported in the literature by 1996 but more are being presented in abstract form. We reviewed our own 33 cases to assist defining operative decision-making criteria. METHODS: All cases of IPMT between 1989 and 1997 were reviewed for clinical presentation, anatomy by endoscopic retrograde cholangiopancreatography and computed tomography, histologic findings, and long-term outcomes. RESULTS: Our cases were older (65 years) and presented with disease centered mainly in the head of the gland. Clinical presentation was epigastric pain (82%), pancreatitis (56%), weight loss (36%), diabetes (27%), and jaundice (9%). Operations were pancreatectomy in 31 (Whipple n = 15, total n = 5, distal n = 10, local n = 1), bypass only (n = 1), and no operation (n = 1). Malignancy was found in 14 of 33 (42%). Factors significantly associated (P <0.05 Fisher exact test) with malignancy were history of alcohol abuse or death from disease. Jaundice or presence in both MPD and SBD approached a significant association with malignancy but not abdominal pain, weight loss, diabetes, preoperative serum elevations of amylase, SGOT, CA-19-9, or CEA; diffuse MPD dilation, gland region, gross mucus in ducts or filling defects, cytology, calcifications, or a pancreatic mass. In 31 resected patients after a follow-up of 37 months (1 to 103) death had occurred in 6 of 13 malignant cases and 0 of 18 with benign disease. Three-year actuarial survival was 82% (all) and 56% (malignant). Symptom recurrence after resection was found in 6 of 31 at a mean of 13 months postoperatively and was associated with death from disease (P <0.05) or presence of pain preoperatively. CONCLUSION: Malignancy is common with IPMT and is more likely to be present with the clinical history of alcohol abuse or jaundice and if the tumor involves both the MPD and the SBD. The prognosis after resection is better than pancreatic cancer but the 19% recurrence of symptoms was equally seen with benign or malignant cases owing to residual disease in pancreatic remnants. The amount of resection should be extensive in patients likely to have malignancy (alcohol, jaundice, MPD+SBD). In those likely to redevelop symptoms, ie, those with preoperative pain, a careful assessment should be made via imaging studies for extent of disease.

The prognosis of resected lung carcinoma associated with atypical adenomatous hyperplasia: a comparison of the prognosis of well-differentiated adenocarcinoma associated with atypical adenomatous hyperplasia and intrapulmonary metastasis.

BACKGROUND: Radiologically undetected intrapulmonary solitary nodules are sometimes found in the resected lung. When the main tumor is a well-differentiated (w/d) adenocarcinoma, especially a bronchioloalveolar carcinoma (BAC), it can be difficult to determine morphologically whether the intrapulmonary nodules are atypical adenomatous hyperplasia (AAH) or intrapulmonary metastasis (PM). The authors evaluated the accuracy of the differential diagnosis of these two lesions from the prognostic point of view. METHODS: A retrospective study was conducted of 1360 lung carcinoma patients who had undergone surgical resection. Differential diagnosis was made between AAH and PM based on the conventional histologic specimens. Their clinicopathologic features were also studied. Survival rates were compared between these two groups. RESULTS: AAH was found in 137 patients (10%) with resected lung carcinoma. The 5-year survival rates were 72.9% in Stage I, 60.6% in Stage II, 27.1% in Stage IIIA, 0% in Stage IIIB, and 0% in Stage IV. They were not significantly different from the figures for all patients in the corresponding pathologic stages. Seventy-six cases were diagnosed as w/d adenocarcinoma associated with AAH, whereas PM was found in 46 cases of w/d adenocarcinoma. The 5-year survival rates of AAH and PM differed significantly: 64.6% and 35.5%, respectively (P 0.0004). When a comparison was made between cases of pT1-2, N0 w/d adenocarcinoma, most of which were BAC, with PM (n = 22) and those with AAH (n = 52), the latter had significantly better survival (P = 0.0086). CONCLUSIONS: The prognosis of resected lung carcinoma was not affected by association with AAH. The significant difference in prognosis between AAH and PM in w/d adenocarcinoma, especially in BAC, indicates that their morphologic distinction was correctly made by conventional pathologic examination in most cases.