Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real-World Data from the Spanish Tumor Registry (R-GETNE).

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs. SUBJECTS, MATERIALS, AND METHODS: A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 <2%), G2 (Ki-67 3%-20%), or G3 (Ki-67 >20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3. RESULTS: Five-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%-5%], 72% [Ki-67 6%-10%], 52% [Ki-67 11%-20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%-50%], 22% [Ki-67 51%-100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%). CONCLUSION: Substantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index. IMPLICATIONS FOR PRACTICE: Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.

Revisión a partir de un caso clínico: flegmasia cerulea dolens / Flegmasia cerulea dolens: clinical case and literature review

La Flegmasia Cerulea Dolens (FCD) es una complicación poco frecuente de la trombosis venosa profunda extensa. Caracterizada por edema masivo, dolor intenso y cianosis. En la trombosis y oclusión aguda de los troncos venosos proximales (ilíacas, vena cava inferior), la congestión puede alcanzar gran severidad, con atrapamiento masivo de líquido intersticial, lo que puede llevar a oliguria y al shock. La extremidad adquiere un aspecto céreo (flegmasia cerulea dolens) por compromiso del drenaje venoso de la extremidad. El aumento de presión intersticial puede llegar a interferir con la perfusión arterial, dando un color pálido (flegmasia alba dolens) e incluso producir isquemia distal en el pie (gangrena venosa), con una alta mortalidad asociada. Hasta el momento, no existe consenso en su tratamiento, la anticoagulación con heparina, trombectomía quirúrgica, terapia trombolítica, fasciotomía y la amputación han sido algunos de los tratamientos propuestos. Presentamos una revisión de flegmasia cerulea dolens en relación a un caso clínico.

The Phlegmasia caerulea dolens (PCD) is an uncommon, severe form of deep venous thrombosis. Characterized by massive edema, severe pain and cyanosis. In the acute thrombosis and occlusion of major venosus channels (iliac and cava inferior) the congestion can reach a massive intersticial fluid secuestration, that can lead to a oliguria and to a shock. The leg acquires a cereo aspect (phlegmasia caerulea dolens) by significantly compromised venous outflow. The increase of the interstitial pressure can interfere with the arterial perfusion, giving a pale color (phlegmasia alba dolens) and can even produce distal ischemia on the foot (venous gangrene), that is a cause of high mortality. Until now, there are no consensus about its treatment. Anticoagulation with heparin, surgical thrombectomy, trombolysis therapy, fasciotomy and amputation had been some of the purposed treatments. We present a review, related to a clinical case, of the Phlegmasia caerulea dolens.