Cases of appendiceal cancer tripled for Americans born between 1976 to 1984 and quadrupled for those born between 1981 to 1989, according to a study published June 9 in the Annals of Internal Medicine. 

The study compared chronological data in five-year intervals from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program, using 1941 to 1949 as the baseline. The lead author, Andreana Holowatyj, PhD, MSCI, assistant professor of Medicine at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, said the findings reveal the need for increased awareness about appendiceal cancer from both clinicians and the public as well as more research to determine the reasons for the sharp spike in incidence.  

“When you take these alarming rates that we are seeing for appendiceal cancer across generations, together with the fact that 1 in every 3 patients diagnosed with appendiceal cancer is diagnosed under the age of 50, these point to a timely need for everyone to be aware of the signs and symptoms of appendix cancer.

“Albeit cancer of the appendix is rare, it is important for individuals who have these symptoms to see a health care professional. Ruling out the possibility of an appendix cancer diagnosis, or diagnosing it early, is important for this cancer as we continue to learn what factors may be contributing to this worrisome trend,” Holowatyj said.

Symptoms may include abdominal pain, bloating, changes in bowel habits, and loss of appetite. 

Appendiceal cancer is a rare cancer with about 3,000 new cases diagnosed every year in the United States, according to prior studies, but Holowatyj and colleagues took a closer look at statistics by combing through the SEER database. 

“As incidence rates in younger generations are often indicative of future disease burden, these results support the need for histology-specific investigations of appendiceal adenocarcinoma, as well as increased education and awareness of appendiceal adenocarcinomas among health care providers and the public,” the study stated. 

Appendiceal cancer has had no standardized screening guidelines, risk factors or tumor classifications — a lack of clinical evidence that has resulted in late diagnosis and poor prognosis. Up to 1 of every 2 patients is diagnosed with distant metastatic disease, and five-year survival rates vary between 10% and 63%.  

Earlier this year, Holowatyj and a team of experts identified six key research priority areas to deliver a fundamental understanding of appendiceal tumors and to improve treatments and outcomes for patients.  

The recommendations published Feb. 20 in Nature Reviews Cancer are the result of a concerted focus by the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation to better understand the disease that afflicts an estimated 3,000 new patients across all age groups each year. 

The recommendations arose from the inaugural ACPMP Research Foundation Scientific Think Tank, sponsored by ACPMP and chaired by Holowatyj at Vanderbilt-Ingram Cancer Center in December 2023. 

The current study in the Annals of Internal Medicine received support from ACPMP and the National Institutes of Health (grants K12HD043483 and P50CA236733). 

Other authors on the study are Mary Kay Washington, MD, PhD, professor of Pathology, Microbiology and Immunology at VUMC, Richard Goldberg, MD, of the West Virginia University School of Medicine, and Caitlin Murphy, PhD, MPH, of the UT Health Houston School of Public Health. 

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Andreana Holowatyj, PhD, MSCI, assistant professor of Medicine, has been named to the 40 Under 40 In Cancer Class of 2025 by the Association for Value-Based Cancer Care.

This year’s class was selected from more than 3,000 nominations. The awards initiative identifies and recognizes contributions across the field of cancer by rising stars and emerging leaders under the age of 40. 

Holowatyj’s research is focused on early-onset cancers, including colorectal and appendiceal cancers. She has received the National Cancer Institute’s Method to Extend Research in Time (MERIT) Award to support her ongoing investigation into how early-onset colorectal cancer and its treatments impact reproductive health. MERIT Awards provide longer-term funding than is typical for most grants to early-stage investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. As part of this Award, Holowatyj established and leads the Preserving Fertility After Colorectal Cancer (PREFACE) clinical study, which is currently recruiting patients.  

She is focused on providing evidence-based guidance that will ultimately improve clinical care and outcomes for individuals ages 18 to 49 when diagnosed with cancer. Holowatyj and her team discovered that 1 in 2 young cancer patients report that a health care provider involved in their cancer care did not discuss options to preserve fertility prior to starting cancer treatment. 

Her research has been published in high-impact medical research journals and has led to clinical practice changes and revisions to consensus guidelines. She has also been invited to serve on several international committees, including the American Joint Committee on Cancer Lower Gastrointestinal Tract Expert Panel that updates clinical cancer staging systems, the Fight Colorectal Cancer Global Early-Onset Colorectal Cancer Think Tank, and as the inaugural chair of the Scientific Advisory Board for the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation. This year, with the support of the ACPMP Research Foundation, she led an expert recommendation report in the journal Nature Reviews Cancer that identified six key research priority areas to deliver a fundamental understanding of appendiceal tumors and to improve treatments and outcomes for patients with this rare cancer.

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Appendiceal cancer is a rare cancer without standardized screening guidelines, risk factors or tumor classifications — a situation that often results in late diagnosis and poor prognosis.  

Up to 1 of every 2 patients is diagnosed with distant metastatic disease, and five-year survival rates vary between 10% and 63%. A team of experts has identified six key research priority areas to deliver a fundamental understanding of appendiceal tumors and to improve treatments and outcomes for patients. Research to advance treatments for this rare cancer is critical.

The recommendations published Feb. 13 in Nature Reviews Cancer are the result of a concerted focus by the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation to better understand the disease that afflicts an estimated 3,000 new patients across all age groups each year. The incidence could be higher because of the challenges accurately diagnosing the disease and identifying the tumor type, the researchers noted.

“The rising burden of appendiceal cancer has illuminated the rudimentary knowledge gaps — spanning from genomes to generations — in our understanding of this rare cancer. By establishing this first-ever research ‘road map’ for appendiceal tumors, we aim to drive collaborative and transformative research discoveries that ultimately will lead to improvements in disease detection, diagnosis, treatments and outcomes for our patients,” said Andreana Holowatyj, PhD, MSCI, assistant professor of Medicine at Vanderbilt University Medical Center and chair of the Scientific Advisory Board for the ACPMP Research Foundation, the article’s lead author.

The recommendations arose from the inaugural ACPMP Research Foundation Scientific Think Tank, sponsored by ACPMP and chaired by Holowatyj at Vanderbilt-Ingram Cancer Center in December 2023. The Think Tank showcases the benefits for scientific collaborations, for robust investments in rare cancer research, and for informing evidence-based medicine. The ongoing effort continues to be a catalyst for revolutionizing the field of research for appendix cancer.

Twenty leading experts on appendiceal cancer met at the Think Tank, and a study group from that meeting are authors of the article.

“This Think Tank and the subsequent publication mark a watershed moment for appendix cancer research,” said Deborah Shelton, JD, Executive Director of ACPMP Research Foundation and co-author of the article. “For far too long, appendix cancer has remained underfunded and underresearched, leaving patients with limited options. These research priorities provide a clear path forward, and ACPMP is committed to ensuring the necessary funding and resources to propel these efforts.”

The six research priorities:

• Refining histopathological classification – Appendix tumors are not a single entity. Variability of terminology for appendix tumor classification is a challenge due to the rarity of the cancer and supports the need for expert pathology review of appendix tumors among all patients. Consistent application of tumor classification and grading, digitizing histology for tumor detection, and leveraging computational approaches to refine tumor diagnosis are needed.
• Molecular characterization of appendix tumors – The discovery of appendix tumor cells most often occurs postappendectomy when the entire appendix has been removed prior to cancer diagnosis. Preserving and molecular profiling of this tissue are necessary to establish a composite multiomics view of appendiceal tumors.
• Defining the appendiceal tumor microenvironment – A better understanding of the dynamic ecosystem surrounding tumor cells will yield new information for treating appendiceal cancer as well as understanding tumor evolution and disease progression. This information should also be used to contribute to a molecular atlas for appendix tumors.
• Development of disease-specific models – The number of appendix tumor models is extremely limited. Research continues on developing patient-derived organoids to support preclinical testing of new therapeutic drugs.
• Clinical studies of appendix tumors – Collaborative, multicenter efforts — such as the Genetics of Appendix Cancer (GAP) Study at Vanderbilt-Ingram, as well as the development of clinical trials in appendix tumors will yield evidence-based, clinically impactful advancements in this rare cancer.
• Appendix cancer on a population level – Population studies will help researchers identify potential risk factors and/or exposures associated with appendix tumors and address distinct care needs of patients with appendix tumors. These studies will deliver key data to establish early detection strategies, support clinical trials, improve clinical practice and impact public policy.

The study’s other authors include Michael Overman, MD, Konstantinos Votanopoulos, MD, PhD, Andrew Lowy, MD, Patrick Wagner, MD, Mary Kay Washington, MD, PhD, Cathy Eng, MD, Wai Chin Foo, MD, Richard Goldberg, MD, Mojgan Hosseini, MD, Kamran Idrees, MD, MSCI, MMHC, Douglas Johnson, MD, MSCI, Ardaman Shergill, MD, Erin Ward, MD, and Nicholas Zachos, PhD.

Their work was supported by the ACPMP Research Foundation, Vanderbilt-Ingram Cancer Center and NIH/NCI (P50CA236733).

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