Classic and Novel Histopathologic Risk Factors for Lymph Node Metastasis in T1 Colorectal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment of endoscopically resected T1 colorectal cancers is based on the risk of lymph node metastasis. Risk is based on histopathologic features, although there is lack of consensus as to what constitutes high-risk features. OBJECTIVE: The purpose of this study was to conduct a systematic review and meta-analysis of histopathologic risk factors for lymph node metastasis. DATA SOURCES: A search of MEDLINE, Embase, Scopus, and Cochrane controlled register of trials for risk factors for lymph node metastasis was performed from inception until August 2018. STUDY SELECTION: Included patients must have had an oncologic resection to confirm lymph node status and reported at least 1 histopathologic risk factor. INTERVENTION: Rates of lymph node positivity were compared between patients with and without risk factors. MAIN OUTCOME MEASURES: We report the results of the meta-analysis as ORs. RESULTS: Of 8592 citations, 60 met inclusion criteria. Pooled analyses found that lymphovascular invasion, vascular invasion, neural invasion, and poorly differentiated histology were significantly associated with lymph node metastasis, as were depths of 1000 µm (OR = 2.76), 1500 µm (OR = 4.37), 2000 µm (OR = 2.37), submucosal level 3 depth (OR = 3.08), and submucosal level 2/3 (OR = 3.08) depth. Depth of 3000 µm, Haggitt level 4, and widths of 3000 µm and 4000 µm were not significantly associated with lymph node metastasis. Tumor budding (OR = 4.99) and poorly differentiated clusters (OR = 14.61) were also significantly associated with lymph node metastasis. LIMITATIONS: Included studies reported risk factors independently, making it impossible to examine the additive metastasis risk in patients with numerous risk factors. CONCLUSIONS: We identified 1500 µm as the depth most significantly associated with lymph node metastasis. Novel factors tumor budding and poorly differentiated clusters were also significantly associated with lymph node metastasis. These findings should help inform guidelines regarding risk stratification of T1 tumors and prompt additional investigation into the exact contribution of poorly differentiated clusters to lymph node metastasis.

Malignant Colorectal Polyp Pathology: Are We Getting Sufficient Information to Make Decisions?

BACKGROUND: The College of American Pathologists has published guidelines for malignant colorectal polyp pathology reports that list histopathological features that are "core elements" and "optional." Lack of element reporting may result in inaccurate tumor risk stratification.This study aimed to perform a population-based assessment of pathology reporting for T1 colorectal cancers and determine the completeness of reporting for core and optional histopathological elements.This is a retrospective cohort study.This study reviews the pathology reports of endoscopically resected malignant colorectal polyps in Alberta, Canada between 2014 and 2016.Individuals aged 18 years or older with T1 colorectal polyps were selected.Histopathological elements were dichotomized into core and optional. Malignant polyps were classified as high risk or low risk for lymph node metastases and local intraluminal recurrence. Addendum reports were compared with first reports.After applying exclusion criteria, 431 polyps were analyzed. The mean age of patients was 65.5 years; 59.4% were male. Histological grade, deep margin, and lymphovascular invasion were reported in 82.4%, 86.8% and 75.6%; all 3 were reported in only 66.4%. Tumor budding (not in the 2016 guidelines) was reported in 14.4%. One hundred ninety polyps (44.1%) were high risk. Thirty-seven polyps (8.3%) had an addendum report. Following the addendum, 1 polyp was downgraded to low risk, and 9 polyps were upgraded to high risk.The main limitation of the study is its retrospective nature. The decision making surrounding treatment for T1 cancers is complex, and factors other than histopathological tumor features may have been part of treatment decisions.There is a high rate of incomplete reporting of core and optional elements for malignant colorectal polyp pathology reports in Alberta. Several variables used by colorectal surgeons for decision making, such as tumor budding and depth of submucosal invasion, are not considered core elements and are infrequently reported. A pathology review by a second pathologist often results in a change in risk stratification. See Video Abstract at http://links.lww.com/DCR/B98. PATOLOGÍA DEL PÓLIPO COLORRECTAL MALIGNO: ¿ESTAMOS OBTENIENDO INFORMACIÓN SUFICIENTE PARA TOMAR DECISIONES?: El Colegio de Patólogos Americanos publico pautas para informes de patología de pólipos colorrectales malignos que enumeran características histopatológicas como "elementos centrales" y "opcionales". La falta de información elemental puede resultar en una estratificación de riesgo tumoral imprecisa.Valoración basada en una población de los informes de patología para los cánceres colorrectales T1 y determinar la precisión de los informes en cuanto los elementos histopatológicos centrales y opcionales.Estudio de cohorte retrospectivo.Este estudio revisa los informes de patología de pólipos colorrectales malignos resecados endoscópicamente en Alberta, Canadá, entre 2014 y 2016.personas mayores de 18 años con pólipos colorrectales T1.Los elementos histopatológicos se dicotomizaron entre elementales y opcionales. Pólipos malignos se clasificaron como de alto riesgo o bajo riesgo de metástasis en los ganglios linfáticos y recurrencia intraluminal local. Los informes enmendados se compararon con los informes originales.Después de aplicar los criterios de exclusión, se analizaron 431 pólipos. La edad media fue 65.5 años, con 59.4% masculinos. El grado histológico, el margen profundo y la invasión linfovascular se informaron confirmaron en 82.4%, 86.8% y 75.6% respectivamente; las tres características se demostraron en solo 66.4%. Un patrón tumoral en ciernes se reporto en 14.4-una característica que no se usaba en las guías de 2016. Ciento noventa pólipos (44.1%) eran de alto riesgo. Treinta y siete pólipos (8.3%) requirieron de un informe enmendado. Aplicación de los nuevos criterios resulto en que 1 pólipo se redujo a bajo riesgo y 9 pólipos se actualizaron como a alto riesgo.La principal limitación del estudio es el diseño retrospectivo. La toma de decisiones en torno al tratamiento de los cánceres T1 es compleja y otros factores además de las características histopatológicas del tumor pueden haber sido parte de las decisiones terapéuticas.Hay una alta tasa de informes incompletos de elementos centrales y opcionales para informes de patología de pólipos colorrectales malignos en Alberta. Algunas variables utilizadas por los cirujanos colorrectales para la toma de decisiones, como el patrón tumoral en ciernes y la profundidad de la invasión submucosa, no se consideran elementos centrales y se informan con poca frecuencia. Una revisión de patología realizada por un segundo patólogo a menudo resulta en un cambio en la estratificación del riesgo. Consulte Video Resumen en http://links.lww.com/DCR/B98. (Traducción-Dr. Adrian E. Ortega).

Hormone phase influences sympathetic responses to high levels of lower body negative pressure in young healthy women.

We tested the hypothesis that sympathetic responses to baroreceptor unloading may be affected by circulating sex hormones. During lower body negative pressure at -30, -60, and -80 mmHg, muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were recorded in women who were taking (n = 8) or not taking (n = 9) hormonal contraceptives. All women were tested twice, once during the low-hormone phase (i.e., the early follicular phase of the menstrual cycle and the placebo phase of hormonal contraceptive use), and again during the high-hormone phase (i.e., the midluteal phase of the menstrual cycle and active phase of contraceptive use). During baroreceptor unloading, the reductions in stroke volume and resultant increases in MSNA and total peripheral resistance were greater in high-hormone than low-hormone phases in both groups. When normalized to the fall in stroke volume, increases in MSNA were no longer different between hormone phases. While stroke volume and sympathetic responses were similar between women taking and not taking hormonal contraceptives, mean arterial pressure was maintained during baroreceptor unloading in women not taking hormonal contraceptives but not in women using hormonal contraceptives. These data suggest that differences in sympathetic activation between hormone phases, as elicited by lower body negative pressure, are the result of hormonally mediated changes in the hemodynamic consequences of negative pressure, rather than centrally driven alterations to sympathetic regulation.

Menstrual cycle and sex effects on sympathetic responses to acute chemoreflex stress.

This study aimed to examine the effects of sex (males vs. females) and sex hormones (menstrual cycle phases in women) on sympathetic responsiveness to severe chemoreflex activation in young, healthy individuals. Muscle sympathetic nerve activity (MSNA) was measured at baseline and during rebreathing followed by a maximal end-inspiratory apnea. In women, baseline MSNA was greater in the midluteal (ML) than early-follicular (EF) phase of the menstrual cycle. Baseline MSNA burst incidence was greater in men than women, while burst frequency and total MSNA were similar between men and women only in the ML phase. Chemoreflex activation evoked graded increases in MSNA burst frequency, amplitude, and total activity in all participants. In women, this sympathoexcitation was greater in the EF than ML phase. The sympathoexcitatory response to chemoreflex stimulation of the EF phase in women was also greater than in men. Nonetheless, changes in total peripheral resistance were similar between sexes and menstrual cycle phases. This indicates that neurovascular transduction was attenuated during the EF phase during chemoreflex activation, thereby offsetting the exaggerated sympathoexcitation. Chemoreflex-induced increases in mean arterial pressure were similar across sexes and menstrual cycle phases. During acute chemoreflex stimulation, reduced neurovascular transduction could provide a mechanism by which apnea-associated morbidity might be attenuated in women relative to men.

Hormone phase dependency of neural responses to chemoreflex-driven sympathoexcitation in young women using hormonal contraceptives.

Hormone fluctuations in women may influence muscle sympathetic nerve activity (MSNA) in a manner dependent on the severity of the sympathoexcitatory stimulus. This study examined MSNA patterns at rest and during chemoreflex stimulation in low- (LH) vs. high-hormone (HH) phases of contraceptive use in healthy young women (n = 7). We tested the hypothesis that MSNA would be greater in the HH phase at baseline and in response to chemoreflex stimulation. MSNA recordings were obtained through microneurography in LH and HH at baseline, during rebreathing causing progressive hypoxia and hypercapnia, and during a hypercapnic-hypoxic end-inspiratory apnea. Baseline MSNA burst incidence (P = 0.03) and burst frequency (P = 0.02) were greater in the HH phase, while MSNA burst amplitude distributions and hemodynamic measures were similar between phases. Rebreathing elicited increases in all MSNA characteristics from baseline (P < 0.05), but was not associated with hormone phase-dependent changes to MSNA patterns. Apnea data were considered in two halves, both of which caused large increases in all MSNA variables from baseline in each hormone phase (P < 0.01). Increases in burst incidence and frequency were greater in LH during the first half of the apnea (P = 0.03 and P = 0.02, respectively), while increases in burst amplitude and total MSNA were greater in LH during the second half of the apnea (P < 0.05). These results indicate that change in hormone phase brought on through use of hormonal contraceptives influences MSNA patterns such that baseline MSNA is greater in the HH phase, but responses to severe chemoreflex stimulation are greater in the LH phase.