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  • Expert Recommendation
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Defining a ‘cells to society’ research framework for appendiceal tumours

Nature Reviews Cancer volume 25, pages 293–315 (2025)Cite this article

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Abstract

Tumours of the appendix — a vestigial digestive organ attached to the colon — are rare. Although we estimate that around 3,000 new appendiceal cancer cases are diagnosed annually in the USA, the challenges of accurately diagnosing and identifying this tumour type suggest that this number may underestimate true population incidence. In the current absence of disease-specific screening and diagnostic imaging modalities, or well-established risk factors, the incidental discovery of appendix tumours is often prompted by acute presentations mimicking appendicitis or when the tumour has already spread into the abdominal cavity — wherein the potential misclassification of appendiceal tumours as malignancies of the colon and ovaries also increases. Notwithstanding these diagnostic difficulties, our understanding of appendix carcinogenesis has advanced in recent years. However, there persist considerable challenges to accelerating the pace of research discoveries towards the path to improved treatments and cures for patients with this group of orphan malignancies. The premise of this Expert Recommendation article is to discuss the current state of the field, to delineate unique challenges for the study of appendiceal tumours, and to propose key priority research areas that will deliver a more complete picture of appendix carcinogenesis and metastasis. The Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation Scientific Think Tank delivered a consensus of core research priorities for appendiceal tumours that are poised to be ground-breaking and transformative for scientific discovery and innovation. On the basis of these six research areas, here, we define the first ‘cells to society’ research framework for appendix tumours.

Key points

  • The rarity of appendiceal tumours present a plethora of unique challenges, inclusive of the following: inaccuracies in accurately capturing disease incidence and prevalence, difficulties with the ascertainment of representative tumour tissues, limited funding opportunities, insufficiency of models and techniques to study appendix pathogenesis and metastasis, and poorly understood heterogeneity across tumour histologies.

  • Defining the continuum of appendiceal tumour histopathological features — utilizing both digital and computational pathology approaches — is poised to expand access for both patients and pathologists, to support current classification and grading criteria, and to potentially deliver molecular predictions and/or novel classifications in appendiceal tumours that can heighten clinical accuracy.

  • Comprehensive molecular profiling of primary and metastatic appendiceal tumours is essential to delivering a complete picture of appendix tumour pathophysiology and for downstream mechanistic and preclinical studies and therapeutic target discovery. Understanding normal appendix epithelium may also reveal why certain tumour histologies (for example, low-grade mucinous neoplasms and goblet cell adenocarcinomas) are virtually unique to the appendix.

  • Evolution of the dynamic and complex ecosystem surrounding appendiceal tumour cells in the primary and metastatic disease setting — the tumour microenvironment (TME) — largely remains an enigma. Disentangling this complex biological interplay within the TME may deliver a new array of rational and potentially combinatorial therapeutic strategies for targeting appendix tumours.

  • The interrogation of appendix tumour biology and advancement in the rate of clinical translation in this disease space is a requisite research need reliant on the establishment of appropriate in vitro, in vivo and computational model systems that are representative of diverse tumour histologies, patient characteristics and the TME.

  • Informing clinical practice patterns and evidence-based medicine for appendiceal tumours is consequent on the conduct of prospective clinical investigations — including cohort, behavioural and health services studies — and clinical trials that address unique considerations of this tumour type.

  • Characterizing the appendix tumour burden on a population level is a priority area that will, in time, deliver evidence to support primary cancer prevention and risk assessment, early detection strategies, improved survivorship and health outcomes, and optimal cancer care delivery to diverse communities.

  • Revolutionizing collaborative research in rare appendiceal tumours — inclusive of robust funding investments and transdisciplinary scientific partnerships — will undoubtedly drive this field towards improving therapies and outcomes for this growing patient population and will also chart a ‘blueprint’ for promising strategies that can be extended into other rare cancer types.

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Fig. 1: Histology of the normal appendix.
Fig. 2: The primary and metastatic appendix tumour ecosystems.
Fig. 3: A ‘cells to society’ research framework for appendix tumours.
Fig. 4: Crosstalk between Gαs and KRAS signalling.
Fig. 5: Care framework for patients with appendix tumours.

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Acknowledgements

The authors thank J. C. Cusack, U. N. Maduekwe and J. P. Y.C. Shen for their intellectual contributions to the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation inaugural Scientific Think Tank. The authors also thank R. Babyak, R. A. Francis, N. Dadgar, D. Gress and A. E. Adams for their technical assistance. Furthermore, the authors extend their sincere gratitude to K. Dobson and M. Yerkes for sharing their individual stories with appendix cancer. This work was supported by the ACPMP Research Foundation and, in part, by the Vanderbilt-Ingram Cancer Center and by the National Institutes of Health-National Cancer Institute grant P50 CA236733.

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Andreana N. Holowatyj, Cathy Eng & Douglas B. Johnson

  2. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Andreana N. Holowatyj, Mary K. Washington, Cathy Eng, Kamran Idrees, Douglas B. Johnson & Nicholas C. Zachos

  3. Vanderbilt University School of Medicine, Nashville, TN, USA

    Andreana N. Holowatyj

  4. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael J. Overman

  5. Division of Surgical Oncology, Department of Surgery, Wake Forest Baptist Health, Winston Salem, NC, USA

    Konstantinos I. Votanopoulos

  6. Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    Andrew M. Lowy

  7. Division of Surgical Oncology, Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA

    Patrick Wagner

  8. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Mary K. Washington

  9. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Wai Chin Foo

  10. West Virginia University Cancer Institute, Morgantown, WV, USA

    Richard M. Goldberg

  11. Department of Pathology, University of California, San Diego, San Diego, CA, USA

    Mojgan Hosseini

  12. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

    Kamran Idrees & Nicholas C. Zachos

  13. Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA

    Ardaman Shergill

  14. Section of Surgical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Erin Ward

  15. Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation, Springfield, PA, USA

    Deborah Shelton

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  1. Andreana N. Holowatyj
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Consortia

on behalf of Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation

  • Andreana N. Holowatyj
  • , Michael J. Overman
  • , Konstantinos I. Votanopoulos
  • , Andrew M. Lowy
  • , Patrick Wagner
  • , Mary K. Washington
  • , Cathy Eng
  • , Wai Chin Foo
  • , Richard M. Goldberg
  • , Mojgan Hosseini
  • , Kamran Idrees
  • , Douglas B. Johnson
  • , Ardaman Shergill
  • , Erin Ward
  • , Nicholas C. Zachos
  •  & Deborah Shelton

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Andreana N. Holowatyj.

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Competing interests

A.N.H. is Chair of the Scientific Advisory Board for the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation and is on the American Joint Committee on Cancer Lower Gastrointestinal Tract Expert Panel and the Peritoneal Surface Malignancies Consortium. A.N.H. reports receiving grants from the National Institutes of Health, American Cancer Society, ACPMP Research Foundation, Dalton Family Foundation and Pfizer. A.N.H. also reports receiving consulting fees from MJH Life Sciences and Bayer outside the submitted work. M.J.O. and K.I.V. are Scientific Advisory Board members for the ACPMP Research Foundation. M.J.O. reports receiving research funding from Takeda, Roche, Lilly, Merck, Medimmune, Bristol–Myers Squibb (BMS), Nouscom and Phanes. M.J.O. also reports consulting fees from Roche, Astellas, Medimmune, Merck, Amgen, Takeda, Janssen, Pfizer, Array, Gritstone, Simcere, Atreca and Bayer. K.I.V. reports receiving grants from the National Institutes of Health and ACPMP Research Foundation. K.I.V. also reports financial interests as the Chief Executive Officer and Founder of Applied Organoids. A.M.L. is a Medical Advisory Board member for the ACPMP Research Foundation and reports receiving grants from the Levine Family Chancellor’s Endowed Chair in Surgical Oncology, National Institutes of Health, and Department of Defense, as well as generous gifts from the estate of Elisabeth and Ad Creemers, the Euske Family Foundation, the Gastrointestinal Cancer Research Fund and the Peritoneal Metastasis Research Fund at the University of California, San Diego. P.W. reports receiving grants from the Pittsburgh Foundation and the ACPMP Research Foundation. R.M.G. reports personal fees from Adaptimmune, AstraZeneca, Bayer, Compass Therapeutics, Focal Medical, G1 Therapeutics, Genentech, GlaxoSmithKline, Haystack Oncology, Innovative Cellular Therapeutics, Merck, Sorrento Therapeutics, Taiho Oncology, Takeda, Valar Technologies and Wolters Kluwer Health outside the submitted work. R.M.G. also reports owning stock options in Focal Medical, Haystack Oncology and Compass Therapeutics. D.B.J. has served on advisory boards or as a consultant for AstraZeneca, BMS, The Jackson Laboratory, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, Targovax and Teiko; has received funding from BMS and Incyte; and has patents pending for the use of MHC-II as a biomarker for immune checkpoint inhibitor response and for abatacept as treatment for immune-related adverse events. A.S. has served on advisory boards for Merus, Guardant, Pfizer, Regeneron/Sanofi and Catalyst Pharmaceuticals. A.S. also reports receiving funding (to the University of Chicago Medical Center) from Hutchison MediPharma, Takeda, Merck, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, BMS, Pfizer, Astellas, Oncologie, Macogenics, Seattle Genetics, Amgen, Daiichi, Lilly, Jacobio, Astrazeneca, Jazz Pharma and Agenus. N.C.Z. reports receiving grants from the National Institutes of Health, Department of Defense, and Eli Lilly and Company. D.S. is a volunteer Executive Director and Board member for the ACPMP Research Foundation. W.C.F., C.E., M.K.W., M.H., K.I. and E.W. declare no competing interests.

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Glossary

Appendectomy

A surgical procedure to remove the appendix, a small, finger-shaped organ originating in the colon (large bowel), located in the lower right side of the abdomen.

Ascites

Swelling in the peritoneal cavity caused by an abnormal accumulation of abdominal fluid.

Colonoscopy

A procedure in which a flexible instrument is inserted through the anus to examine the inner lining of the colon after cleansing it of stool using a variety of laxative preparative regimens.

Completeness of cytoreduction (CC) score

Assessment of the postoperative extent of peritoneal disease removal.

Complicated appendicitis

Appendicitis associated with necrosis leading to perforation or a periappendicular abscess.

Convolutional neural networks

A mathematical algorithm that analyses visual images by processing data in multiple layers to detect and classify objects in an image.

Cytoreductive surgery

(CRS). A surgical procedure to remove all visible tumours and diseased tissue in the peritoneum.

Dual-modality imaging

The use of two complementary imaging techniques to improve diagnostic accuracy and assessments.

Early-onset appendix tumours

Tumours in individuals between 18 and 49 years of age.

Genetic variants

Changes in DNA sequence between individuals within a population.

Goblet cell

Intestinal epithelial cell that synthesizes and secretes mucus and mucins, named for its goblet cup-like appearance formed by mucin granulae that fill up the cytoplasm.

Hyperthermic intraperitoneal chemotherapy

(HIPEC). A procedure wherein a catheter containing chemotherapeutic drugs is inserted into the abdominal cavity. The catheter is connected to a perfusion machine, which heats the chemotherapy drugs and pumps them through the abdomen.

Intra-operative consultations

With respect to frozen sections. Immediate ad hoc pathologist interpretations that guide surgical management.

Mesothelial cells

A thin layer of cells present on the surface of the peritoneum that allows internal organs to move freely, that secretes lubricants for tissue protection, and that initiates an immune response when encountering tumour cells or foreign organisms.

Microsatellite instability

(MSI). Regions of repeated DNA that change in length when mismatch repair is defective. These deficiencies in DNA mismatch repair can be caused by hereditary, germline mutations or epigenetic silencing by hypermethylation.

Mucin

A family of glycoproteins that are secreted by epithelial cells and form a major component of mucus.

Peritoneal cancer index

(PCI). A scoring system (from 0–39) used to quantify the extent of disease spread into the peritoneal cavity.

Peritoneal washings

A procedure wherein a salt–water solution is used to wash the peritoneal cavity. This solution is then removed to check for cancer cells.

Peritoneum

A protective membrane lining the abdominal cavity that also extends to cover most of the organs in the abdomen.

Pseudomyxoma peritonei

(PMP). Also known as mucinous carcinoma peritonei. A clinical entity characterized by diffuse intra-abdominal gelatinous ascites with mucinous implants on peritoneal surfaces. Mucinous neoplasms of the appendix are the most common, but not the sole, tumour type that can give rise to PMP.

Signet ring cells

(SRCs). Glandular epithelial cells that line digestive organs. Their respective nucleus is shifted to one side by a large cytoplasmic vacuole.

Tumour cellularity

The overall percentage of a tumour that contains neoplastic epithelium with mucinous deposits by visual pathological estimation.

Tumour grade

A qualitative assessment of the degree of tumour differentiation. Grade may reflect the extent to which a tumour resembles normal tissue.

Whole slide imaging

(WSI). The microscopic scanning of whole glass tissue slides to convert them into digital equivalents.

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Holowatyj, A.N., Overman, M.J., Votanopoulos, K.I. et al. Defining a ‘cells to society’ research framework for appendiceal tumours. Nat Rev Cancer 25, 293–315 (2025). https://doi.org/10.1038/s41568-024-00788-2

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