Interobserver variability amongst gastrointestinal pathologists in assessing prognostic parameters of malignant colorectal polyps: a cause for concern.

BACKGROUND: Malignant colorectal polyps (MCRP) have become a major challenge in the field of coloproctology from diagnosis to full treatment. One important facet of the challenge is the histopathological staging of the lesion and identifying various prognostic parameters. The primary aim of this study was to find the interobserver variation amongst 4 experienced gastrointestinal pathologists when assessing important parameters and staging systems (Haggitt, Kikuchi and Ueno) in MCRPs. METHODS: Four experienced gastrointestinal pathologists independently assessed 56 cases of MCRP, and each pathologist completed a pro forma for each case. The results were collated and statistically analysed. RESULTS: There was a significant variation in the assessments using the various published staging systems agreed upon on important prognostic parameters. CONCLUSIONS: None of the staging systems used is suitable for all polyp types or has good reproducibility. There is an urgent need to make pathologists' assessment of MCRPs easier and more reproducible.

Comparison of the prognostic value of the 6th and 7th editions of the Union for International Cancer Control TNM staging system in patients with lower esophageal cancer undergoing neoadjuvant chemotherapy followed by surgery.

Carcinoma of the esophagus is classified according to the Union for International Cancer Control (UICC) TNM staging system. The 7th edition of the UICC TNM staging system was published in 2009. This is the first study to compare the prognostic value of the TNM 6th and 7th editions in patients with esophageal carcinoma treated with chemotherapy followed by surgery. Two hundred forty-three patients with esophageal carcinoma were retrospectively selected from two referral centers. All patients received chemotherapy before surgery. Histopathologic data from the resection specimens were retrieved and restaged according to the TNM 7th edition. Disease-specific survival curves were plotted for depth of tumor invasion (ypT), lymph node status (ypN), and ypTNM stage and then compared. Median follow-up after surgery was 2.5 years (range 0.2-9 years). Survival analysis using the log-rank method revealed that there was a significant difference in survival between ypT4 disease and ypT3 disease (P= 0.003), but no difference between ypT0, ypT1, ypT2, and ypT3 categories irrespective of TNM edition used. Survival probability was significantly different between ypN0 and ypN1 (P= 0.001 for TNM 6th and 7th edition), as well as ypN2 and ypN3 (TNM 7th edition, P= 0.004), but not between ypN1 and ypN2 (TNM 7th edition, P= 0.89). Neither the TNM 6th nor 7th edition T staging provides accurate survival probability stratification. However, the advantage of the 7th edition is the introduction of a third tier in survival stratification for patients with nodal involvement.

The prognostic value of circumferential resection margin involvement in oesophageal malignancy.

AIM: Our aim was to assess the effect on survival of circumferential resection margin (CRM) involvement in patients with resected oesophageal malignancy. METHODS: Patients undergoing potentially curative oesophageal resection between January 1994 and December 2003 were retrospectively analysed. CRM status was defined as either clear or involved (microscopic tumour within 1 mm of the inked resection margin). Univariate and multivariate survival analyses were performed using the Kaplan-Meier method and Cox proportional hazard model. Overall survival was used as the endpoint. RESULTS: The case records of 249 patients were analysed. CRM status was clear in 170 patients (T1-T3 tumours) and involved in 79 patients (all T3 tumours). Median survival in these groups was 37 months (range 28-47) and 18 months (range 13-23), respectively (p = 0.0001). When T3 tumours were analysed separately there was a trend for T3 CRM involved tumours to have a worse prognosis than T3 CRM clear tumours (p = 0.074). Substratification by percentage of lymph nodes involved by metastases (< or = or >25%) revealed that CRM status had a greater prognostic effect in T3 tumours with a low metastatic lymph node burden (p = 0.04). CONCLUSION: CRM involvement predicts poor prognosis in patients with resected oesophageal malignancy and was an independent prognostic factor in our study. There was only a trend for worse prognosis when T3 tumours were analysed separately. However, patients with T3 tumours and a low percentage of lymph node metastases had a better prognosis if the CRM was negative.

Combined endoscopic and laparoscopic approach for palliative resection of metastatic melanoma of the stomach.

BACKGROUND: Metastatic tumours of the stomach present a clinical dilemma for the surgeon. Palliative surgical resection can alleviate symptoms and prolong survival in selected patients. However, previous studies have used open methods of surgical resection with potentially high morbidity and mortality. We describe the use of laparoscopic wedge resection of the stomach for palliative resection of metastatic melanoma to highlight the benefits of this technique. CASE PRESENTATION: A 58 year old male was investigated for iron deficiency anaemia while under treatment for pulmonary metastatic malignant melanoma. An upper gastrointestinal endoscopy revealed a 5 cm diameter ulcer on the anterior wall of the stomach, biopsies from the ulcer confirmed metastatic melanoma. Laparoscopic wedge resection of the stomach lesion was performed without complication. CONCLUSION: Laparoscopic approach has many benefits and is useful for the palliative resection of rare tumours of the stomach in order to preserve the quality of life. Its use should be considered in selected patients.

Is the hypoxia-inducible factor pathway important in gastric cancer?

Tumour hypoxia is well recognised in oncology to be a key factor resulting in treatment resistance and poor prognosis. Hypoxia leads to the expression of a number of gene products that are involved in tumour progression, invasion and metastasis formation. The most important of these proteins is thought to be hypoxia-inducible factor-1alpha (HIF-1alpha), which appears to be a master regulator of the cellular response to hypoxia. HIF-1alpha expression is associated with a poor prognosis and treatment response in a number of tumour sites. There is some evidence that the HIF-1alpha pathway might be involved in gastric carcinogenesis. Studies have shown reactive oxygen species from Helicobacter pylori, associated with the development of gastric cancer, stabilise HIF-1alpha. Non-steroidal anti-inflammatory drugs, shown to reduce the risk of gastric cancer, can decrease HIF-1alpha expression. Although a large study correlating HIF-1alpha expression with prognosis is lacking in gastric cancer, the immunohistochemical expression of HIF-1alpha target genes (Glut-1, VEGF, CA9, iNOS) is associated with a poor prognosis. In addition, the targeted inhibition of HIF-1alpha has been shown to inhibit the growth of gastric tumours in animals. Increased understanding of the importance of hypoxia and the HIF-1alpha pathways may therefore hold the key to prevention strategies, improved selection of patients for adjuvant therapy and new treatments for the disease.

How often does maternal preeclampsia-eclampsia incite thrombocytopenia in the fetus?

Overt thrombocytopenia (defined as a platelet count of less than 100,000/microL) was not identified at or soon after delivery in any of 262 infants of mothers with hypertension induced or exacerbated by pregnancy. The platelet counts were 100,000 to 149,000/microL in 11 (4.2%) of the offspring and 150,000/microL or higher in the rest, even though the platelet counts of the 258 mothers were less than 150,000/microL in 77 (30%), less than 100,000/microL in 51 (20%), and less than 50,000/microL in 17 (7%). Some infants of hypertensive mothers did develop overt thrombocytopenia later; however, the frequency and intensity appeared to be no greater than it was in infants with similar complications (prematurity, growth retardation, infection, and meconium aspiration) whose mothers were normotensive. We conclude that the fetus whose mother has preeclampsia-eclampsia is very unlikely to be thrombocytopenic during labor and delivery, even when the mother is thrombocytopenic. Therefore, neither cesarean delivery to avoid labor nor scalp blood platelet counts during labor need be performed.

Clinical impact of tumour involvement of the anastomotic doughnut in oesophagogastric cancer surgery.

INTRODUCTION: Published colorectal cancer surgery data suggest no role for the analysis of the anastomotic doughnuts following anterior resection. The usefulness of routine histological analysis of the upper gastrointestinal doughnut is not clear. Our study assessed the impact of cancer involvement of the doughnut on clinical practice. Factors associated with doughnut involvement and the effect on patients' survival were also analysed. PATIENTS AND METHODS: The clinicopathological details of 462 patients who underwent potentially curative oesophagogastrectomy for cancer with a stapled anastomosis between 1994 and 2006 in two specialist centres were retrospectively analysed. Univariate, multivariate and survival analyses were carried out. RESULTS: Approximately 5% of doughnuts (22 of 462) were histologically involved with cancer. Microscopic involvement of the proximal resection margin, local lymph node metastasis and lymphatic invasion within the main resected specimen were independently associated with doughnut involvement (all P < 0.05). However, these three factors taken together failed to predict doughnut involvement. Doughnut involvement was an independent adverse prognostic factor for overall survival (P = 0.0013). CONCLUSIONS: In contrast to findings in colorectal surgery, doughnut involvement with cancer appears to have useful prognostic information following oesophagogastrectomy. Routine histological analysis of upper gastrointestinal doughnuts is justified. Doughnut involvement could potentially strengthen the indications for adjuvant therapy in the future.

Best practice in macroscopic examination of gastric resections.

Gastric cancer is one of the most common cancers worldwide, with a frequency that varies greatly across different geographic locations. Over recent decades there has been a marked increase in cancers of the oesophagogastric junction, but gastric cancers have shown a decrease in worldwide incidence. However, they still account for 3-10% of all cancer-related deaths. There has been a steady improvement in prognosis in countries such as Japan, predominantly due to screening programmes and early detection, but this has not been seen in Europe and North America. At present the only curative treatment for gastric cancer is complete surgical resection of the primary tumour, with appropriate lymphadenectomy. High quality histology reports are necessary to provide information on diagnosis, prognosis and future management. They can also be important with regard to research, audit and epidemiological studies. This review examines the evidence-based guidelines for macroscopic examination and block selection for gastric carcinomas, with a brief comment on new surgical techniques.

Hypoxia-associated markers in gastric carcinogenesis and HIF-2alpha in gastric and gastro-oesophageal cancer prognosis.

The study investigated hypoxia-associated markers (HIF-2alpha, Epo, Epo-R, Glut-1 and VEGF) along with Ki-67 in a gastric carcinogenesis model, and the prognostic significance of hypoxia-inducible factor (HIF)-2alpha in surgically treated gastro-oesophageal cancer. Protein expression was examined using immunohistochemistry on formalin-fixed, paraffin-embedded biopsies of normal mucosa (n=20), Helicobacter pylori-associated gastritis (n=24), intestinal metaplasia (n=24), dysplasia (n=12) and intestinal (n=19) and diffuse (n=21) adenocarcinoma. Relationships between HIF-2alpha expression and prognosis were assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Expression of all markers increased with progression along the gastric carcinogenesis sequence (P=0.0001). Hypoxia-inducible factor-2alpha was expressed in 63% of 177 resection specimens and at a high level in 44%. The median overall survival in patients with HIF-2alpha-expressing tumours was 22 (95% CI 18-26) months, whereas those with HIF-2alpha-negative tumours had a median survival of 37 (95% CI 29-44) months (P=0.015). Hypoxia-inducible factor-2alpha had no independent prognostic significance in multivariate analysis. In view of the lack of independent prognostic significance, HIF-2alpha has no role as a routine prognostic indicator. However, the high expression of HIF-2alpha suggests that it may be of value as a potential therapeutic target.

Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence.

Hypoxia-associated markers are involved in the progression of several malignancies, but are relatively unstudied in Barrett's carcinogenesis. Our aim was to assess the immunohistochemical expression of hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, erythropoietin (Epo), Epo receptor (Epo-R), Glut-1 and vascular endothelial growth factor (VEGF) along with Ki67/MIB-1 in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. Endoscopic biopsies of normal squamous epithelium (NSE) (n=20), columnar-lined oesophagus (CLO) (n=15), CLO with intestinal metaplasia (n=20), dysplasia (n=17) and Barrett's type adenocarcinoma (n=20) were obtained. Immunohistochemistry was performed on the paraffin-embedded tissue. A score was calculated for each marker (range 0-300) by multiplying intensity (none 0, weak 1, moderate 2, strong 3) by percentage of expression (range 0-100). Significant increases in the expression of HIF-2alpha (P=0.014), VEGF (P<0.0001), Epo-R (P<0.0001) and Ki67 (P<0.0001) were found as tissue progressed from NSE to adenocarcinoma. HIF-2alpha was expressed late in the sequence and was only seen in dysplasia and adenocarcinoma. High HIF-2alpha expression was seen in 12 out of 20 Barrett's type adenocarcinoma. The late expression of HIF-2alpha in the Barrett's carcinogenesis sequence and its high expression in adenocarcinoma suggest that it is worth further investigation as a marker of disease progression and therapeutic target.

Hypoxia-inducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas.

Hypoxia-inducible factor-1 (HIF-1)alpha expression was studied in the gastric carcinogenesis sequence and as a prognostic factor in surgically resected gastric and gastro-oesophageal junction tumours. Protein expression was examined using immunohistochemistry on formalin-fixed biopsies of normal mucosa (n=20), Helicobacter pylori associated gastritis (n=24), intestinal metaplasia (n=24), dysplasia (n=12) and intestinal (n=19) and diffuse (n=21) adenocarcinoma. The relationship between HIF-1alpha expression and prognosis was assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Hypoxia-inducible factor-1alpha expression was not observed in normal gastric mucosa but increased in density (P<0.01) and intensity (P<0.01) with progression from H. pylori-associated gastritis, intestinal metaplasia, dysplasia to adenocarcinoma. The pattern of staining in the resection specimens was focally positive in 49 (28%) and at the invasive tumour edge in 41 (23%). Invasive edge expression was associated with lymph node metastases (P=0.034), advanced TNM stage (P=0.001) and was an adverse prognostic factor for cancer-specific survival (P=0.019). In univariate analysis and in comparison with tumours not expressing HIF-1alpha, invasive edge staining was associated with a hazard ratio of 1.6 (95% CI 1.0-2.5) and focally positive staining a hazard ratio of 0.7 (95% CI 0.5-1.2). Hypoxia-inducible factor-1alpha lost prognostic significance in multivariate analysis. The results suggest HIF-1alpha is involved in gastric carcinogenesis and disease progression, but is only a weak prognostic factor for survival.

Standardized treatment of 154 consecutive cases of eclampsia.

Since 1955 standardized treatment applied uniformly to all cases of eclampsia at Parkland Memorial Hospital has consisted of (1) magnesium sulfate intravenously and intramuscularly to control convulsions, (2) intravenous hydralazine intermittently to lower diastolic blood pressure when it exceeded 110 mm. Hg, and (3) steps to effect vaginal delivery as soon as the woman has regained consciousness. The dosage schedules for magnesium sulfate and hydralazine, while empiric, have been extensively tested for both efficacy and toxicity. Delivery usually was accomplished vaginally and conduction anesthesia was avoided. Neither diuretics nor osmotic agents in the form of hypertonic glucose, mannitol, or albumin were used to treat eclampsia. Heparin was never given. To date 154 cases of eclampsia have been so treated with no maternal death. All fetuses alive when treatment was started and weighing 1,800 Gm. (4 pounds) or more survived. The results provide a standard against which new drugs and treatment regimens can be compared.

The Parkland Memorial Hospital protocol for treatment of eclampsia: evaluation of 245 cases.

Since 1955, a standardized treatment regimen has been used to manage 245 cases of eclampsia at Parkland Memorial Hospital. Magnesium sulfate alone effectively controlled controlled convulsions in the great majority of cases. The only maternal death among the 245 cases reemphasizes the risk of respiratory arrest that is inherent in the administration of magnesium sulfate when given in large doses intravenously. Hydralazine to lower the diastolic blood pressure somewhat, when it was 110 mm Hg or higher, prevented intracranial hemorrhage. Avoidance of diuretics and hyperosmotic agents and limitation of fluid intake were not associated with severe renal failure. Pulmonary edema was rare. Vaginal delivery was achieved in the majority of cases. Oxytocin often proved effective for initiating and maintaining labor even remote from term. The results obtained with this regimen justify its continued clinical application.

Failure of tubal sterilization accompanying cesarean section.

PIP: Pomeroy tubal resection during cesarean section has had a reputation of a high failure rate, since a report of 7 failures in 400 (Prystowsky et al. Journal of the American Medical Association 158: 463. 1955). In this survey, 400 women sterilized by the Pomeroy technique after cesarean section were followed an average of 6 years. One failure occurred 2.5 years after the operation where there had been histologic evidence of complete section of the tube.^ieng

On reducing the frequency of severe abruptio placentae.

At Parkland Memorial Hospital the frequency of abruptio placentae so severe as to kill the fetus has decreased from 1 in 420 deliveries during 1956 through 1969 to 1 in 830 during 1974 through 1989. Major factors in this reduction were elimination of very high parity and a marked increase in the percentage of Latin American women, in whom the risk was 1 in 1473 deliveries compared with 1 in 595 for black women and 1 in 876 for white women. Abdominal trauma was encountered rarely, as was fetoplacental-to-maternal hemorrhage sufficient to impair fetal perfusion seriously. Abnormal development of Müllerian ducts and uterine myomas were encountered rarely. Neither red blood cell macrocytosis characteristic of folate deficiency nor iron deficiency could be implicated in the genesis of severe abruptio placentae. Abruptio placentae recurred in 12% of subsequent pregnancies and proved fatal to the fetus in 7%, unchanged from our earlier experience.