Dear readers,

In the oncology landscape, gallbladder cancer has long lingered in the shadows, overshadowed by more common forms of cancer. However, its impact on public health is becoming increasingly evident. It is in this context that we dedicate this editorial to highlight the critical importance of researching this pathology.

Gallbladder carcinoma (GBC), although relatively rare, is the most common biliary tree malignancy and constitutes an aggressive and lethal malignancy with a grim prognosis. Each year, 122,491 people are diagnosed with gallbladder cancer, and 89,055 people suffer from this pathology globally ¹. Although 5-year survival rates have progressively increased to between 7% and 20%, patients with advanced disease still have a 5-year survival rate of less than 5% ².

GBC, despite being uncommon in most countries, exhibits notable geographical variability ³. Differences in the geographical distribution of incidence can be explained by various factors: genetic mutations, socioeconomic status, and environmental factors ^4,5. Nearly 40% of countries with the highest incidence rates (15 out of 38 countries with rates ≥1.3/100,000) are located in South America, South Asia, and Southeast Asia. Indigenous populations in South America (particularly in the Andean region ), northern India, and East Asia have particularly high rates of gallbladder cancer ^3,6.

The prognosis is not encouraging as there is an estimated substantial increase in GBC rates by 2040 due to population aging and obesity ^2,5,6. Generally, gallbladder cancer is primarily observed in older individuals (average age at diagnosis: 72 years), but it can also develop in younger people ⁷. In the study "Prevalence of gallbladder cancer in post-cholecystectomy patients in a Third Level Hospital in 2021 in Paraguay" published in this edition, the average age of the 65 cholecystectomized patients was 39 years (range: 14-77 years), among whom 2 patients were diagnosed with poorly differentiated carcinomas; it would be interesting to precisely define the age of individuals with GBC in Paraguay considering that most people worldwide are 65 years or older when this pathology is detected.

GBC is a silent and ruthless disease often diagnosed in advanced stages, drastically reducing treatment options and survival rates. Prophylactic cholecystectomy is one of the strategies proposed by some groups in Latin America to decrease mortality, but its cost-effectiveness is questionable ^6,8. One way to improve the performance of prophylactic cholecystectomy would be to identify molecular risk factors that, in combination with those currently known, detect patients at very high risk of developing gallbladder cancer. Currently, the available information regarding the molecular biology of biliary cancer, including GBC, is very limited, even more so in South America ^1,9.

Among the known risk factors for gallbladder cancer, chronic inflammation of the gallbladder is a common link among many ¹⁰. For example, in the presence of gallstones, the gallbladder releases bile more slowly, leading to prolonged exposure of gallbladder cells to chemicals in bile, causing irritation and inflammation. It is worth noting that in one study published in this editorial "Gallbladder cancer, experience of the General Surgery Service of the Itauguá National Hospital from 2010 to 2020", the main etiology of gallbladder cancer was cholelithiasis as indicated in the literature.

In general, cancer can be caused by changes in DNA (mutations) that activate oncogenes or deactivate tumor suppressor genes. Usually, changes in many different genes are needed for a cell to become cancerous. Some people inherit DNA mutations from their parents that greatly increase their risk of certain cancers such as breast cancer when associated with germline mutations in the BRCA1 and BRCA2 genes. Regarding GBC, genetic mutations related to gallbladder cancers are generally acquired during life rather than inherited. Some of the genetic changes that lead to gallbladder cancer could be caused by chronic inflammation among other factors. Many genetic changes could simply be random events that sometimes occur within a cell, without having an external cause.

Two models have been proposed in GBC: metaplasia to dysplasia and adenoma to dysplasia. The former shows alterations in tumor suppressor genes (CDKN2A, p53, p57, KIP2), adhesion molecules (CEA, CD99), oncogenes (C-erb-B2, KRAS), among others. In the adenoma-carcinoma model, alterations in cell adhesion molecules (CD54 and CD56) and mutations of the CTNNB1, STK11, APC genes have been reported. The metaplasia-dysplasia model (associated with cholelithiasis) is more accepted because these histological alterations are more frequent in GBC compared to adenomatous polyps ^3,6.

Despite the increasing incidence of GBC worldwide, advances in its diagnosis, treatment, and prevention have been notably limited. This underscores the urgency of intensifying research efforts dedicated to better understanding this disease and developing more effective strategies to combat it, especially considering the epidemiological data at the regional level.

On behalf of the Editorial Board of the Faculty of Medical Sciences and the entire scientific community of Paraguay, I would like to express my sincere gratitude to all colleagues who have contributed their research on gallbladder cancer and encourage the entire community to continue researching. Your dedicated and valuable contributions not only enrich our collective knowledge of this pathology but are also essential to advancing the fight against it.

*The highest Age-Standardized Incidence and Mortality Rates have been reported in Bolivia (14.0% and 10.6%, respectively), Chile (9.3% and 5.4%), where GBC is the second leading cause of cancer death in women, and Peru (4.8% and 3.1%).