Gastric adenocarcinoma with peritoneal metastasis (PM) has a poor prognosis, yet clinical outcomes vary significantly. This study aimed to identify independent prognostic determinants of PM-specific survival (PM-OS), focusing on tumor biology and disease burden surrogate. We retrospectively analyzed 166 patients with gastric adenocarcinoma and PM treated at a single center between 2015 and 2024. Prognostic factors were evaluated using multivariable Cox proportional hazards models. To mitigate immortal time bias and confounding by indication, receipt of systemic therapy was excluded from the primary multivariable model. The median PM-OS was 8.2 months (95% CI, 6.63-9.79). Patients diagnosed via surgical exploration (radiologically occult) achieved a significantly longer median PM-OS compared to those diagnosed radiologically (13.6 vs. 7.4 months; p = 0.003). In multivariable analysis, HER2 positivity (HR0.312, 95% CI 0.164-0.593; p < 0.001) and surgical diagnosis (HR 0.555, 95% CI 0.338-0.913; p = 0.020), interpreted as a surrogate for radiologically occult/low tumor burden, were identified as independent predictors of improved survival. Additionally, an optimized CA 19 - 9 cutoff (> 175.4 U/mL), unlike the standard threshold, significantly stratified survival. Traditional factors, including signet-ring cell histology and age, did not retain independent significance.In sensitivity analysis including systemic therapy, treatment was strongly associated with survival and the prognostic significance of HER2 and diagnostic context remained. Survival in gastric PM is fundamentally driven by HER2 status and the extent of PM. Surgical detection identifies a subgroup with limited, occult disease who achieve superior outcomes compared to those with radiologically overt metastases. Furthermore, the magnitude of biomarker elevation, rather than mere positivity, serves as a critical stratifier. These findings support a paradigm shift towards burden-based risk stratification to guide treatment intensity and clinical trial eligibility.

Tumor microenvironment-driven ST6Gal-Ⅰ activation promotes aggressiveness in gastric signet-ring cell carcinoma via ITGβ1/FAK/Paxillin signaling.

Melanoma is traditionally classified into a limited number of common clinicopathologic subtypes; however, routine clinical and histopathologic practice reveals a broad spectrum of rare variants and unusual morphologic patterns that pose significant diagnostic and therapeutic challenges. These uncommon melanomas may closely mimic benign melanocytic proliferations or non-melanocytic neoplasms, present with subtle or atypical clinical and dermoscopic features, and exhibit distinctive biologic behavior and treatment responses. Consequently, their clinical impact is disproportionate to their low incidence. This narrative review provides an updated and integrated overview of rare primary melanoma subtypes, including desmoplastic melanoma, nevoid melanoma, Spitz melanoma, melanoma ex blue nevus, and primary dermal melanoma, as well as uncommon histologic variants such as rhabdoid, metaplastic (osteogenic and chondrogenic), myxoid, small cell, balloon/clear cell, signet-ring cell, and plexiform melanoma. In addition, rare combined cutaneous tumors containing both melanomatous and epithelial components are discussed. For each entity, we summarize current evidence on epidemiology, clinical and dermoscopic presentation, histopathologic features, immunohistochemical profiles, and molecular alterations, with particular emphasis on key diagnostic pitfalls and differential diagnoses. Advances in molecular pathology have refined the classification of these rare melanomas, enabling more precise integration of morphology, immunophenotype, and genomic data, with direct implications for prognosis, staging, and therapeutic decision-making. Finally, we review available data on management strategies, including surgery, sentinel lymph node biopsy, radiotherapy, targeted therapy, and immunotherapy. By synthesizing current knowledge and highlighting practical diagnostic and therapeutic considerations, this review aims to assist pathologists and clinicians in navigating the "grey zones" of melanoma diagnosis, ultimately supporting more accurate classification and more personalized patient care.

The clinical benefit of PD-1/PD-L1-based immunotherapy in gastric signet ring cell carcinoma (GSRCC) remains unclear. This study evaluated the efficacy of first-line immunotherapy in advanced GSRCC. This single-center retrospective cohort study assessed the clinical response of patients with advanced GC diagnosed from November 2019 to January 2025 after receiving first-line immunotherapy combined with chemotherapy and/or target therapy, concurrently comparing therapeutic outcomes in GSRCC and non-GSRCC cohorts. This study included 230 patients, with objective response rate (ORR) achieving 43.9%. Among the 150 non-GSRCC patients, the ORR was 50.7%, compared to 31.3% in the 80 GSRCC patients. Non-GSRCC patients had longer median progression-free survival (PFS: 10.0 vs 7.9 months; p = 0.002) and overall survival (OS: 17.4 vs 15.3 months; p = 0.039). Peritoneal metastasis was independently associated with rapid progression and poor survival (HR 2.63, 95% CI 1.52-5.53; p = 0.001). Among GSRCC patients, those with peritoneal metastasis had significantly shorter PFS (6.6 vs 13.6 months; p < 0.001) and OS (11.0 vs 19.4 months; p = 0.001). The findings suggest that GSRCC is associated with resistance to immunotherapy in advanced GC. Furthermore, peritoneal metastasis is significantly associated with poor prognosis in GSRCC patients.

Leptomeningeal carcinomatosis (LMC) from gastric cancer is rare but carries a poor prognosis, and its risk factors and clinical presentation remain unclear. Among 3850 patients treated with palliative chemotherapy, those with pathologically or cytologically confirmed LMC were included. Responsiveness to intrathecal methotrexate (IT-MTX) was defined as a malignant cell count < 1/μL on ≥ 2 consecutive cerebrospinal fluid analyses. Survival outcomes were compared across subgroups with different clinical presentations. During a median follow-up of 13.7months, LMC was diagnosed in 0.8% (32/3850) of patients. At the time of LMC diagnosis, 27 patients were undergoing palliative systemic chemotherapy, 4 were diagnosed with recurrence following curative surgery, and 1 was diagnosed with the initial presentation of metastatic gastric cancer. Multivariate logistic regression analysis revealed that signet ring cell carcinoma (SRC) and/or poorly differentiated adenocarcinoma (PD) was the most relevant risk factor for LMC (adjusted odds ratio 4.78; p = 0.036). Thirty patients received IT-MTX, with responders (n = 23) showing longer overall survival (OS) than non-responders (n = 7) (p = 0.004). Among the 29 patients with available data on extracranial disease control, those with controlled extracranial disease at LMC diagnosis (n = 19) demonstrated significantly better OS following IT-MTX than those with progressive extracranial disease (n = 10) (p = 0.023). SRC and/or PD is a key risk factor for LMC, which often arises despite controlled extracranial disease, necessitating early evaluation for neurologic symptoms. Survival outcomes depend on IT-MTX response and the status of extracranial disease.

Prognostic value of combined pathological response in primary tumor and lymph nodes after neoadjuvant chemoimmunotherapy for locally advanced gastric cancer.

Now and future of artificial intelligence-based signet ring cell diagnosis: A survey

Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by the early onset of diffuse gastric cancer (DGC) and lobular breast cancer. HDGC is predominantly caused by germline truncating mutations in CDH1, which encodes the cell-cell adhesion protein, E-cadherin. Less frequent predisposing mutations are observed in the CTNNA1 gene that encodes α-catenin. E-cadherin and α-catenin are components of the epithelial adherens junction and play important roles in cell adhesion, signal transduction, and cell architecture maintenance. The first step in DGC initiation in carriers of pathogenic CDH1 and CTNNA1 variants is the inactivation of wildtype CDH1 or CTNNA1 alleles, leading to the development of intramucosal gastric signet ring cell carcinomas (SRCCs). In the case of CDH1 mutations, E-cadherin loss is associated with abnormal orientation of the mitotic spindle, which is believed to result in the displacement of dividing stem or progenitor cells out of the epithelial plane and into either the glandular lumen or lamina propria. Although these early stage pT1a SRCCs are generally indolent, they can acquire aggressive traits that precede a pattern of invasive growth. HDGC is clinically managed using an increasingly balanced approach involving endoscopic surveillance and prophylactic total gastrectomy. In this review, we discuss the range of predisposing germline HDGC variants and their effects, the mechanism of DGC initiation and growth, and current best practices for the diagnosis and management of this disease. Finally, we highlight emerging areas of research on the characterization, classification, and management of HDGC.

Synchronous multiple primary malignancies (MPM) represent an increasingly relevant challenge in oncology due to rising the incidence and complexity of selecting optimal therapy. Germline mutations in BRCA1/2 genes are associated with a higher risk of breast and ovarian cancers and may serve as predictors of sensitivity to systemic therapies, including platinum-based chemotherapy and PARP inhibitors. We present a case of a 63-year-old female patient with MPM, including stage IV serous ovarian carcinoma with metastases in mediastinal lymph nodes, stage IIA breast carcinoma, and signet-ring cell gastric carcinoma stage IIB. Next-generation sequencing (NGS) identified a germline BRCA1 mutation (c.5382_5383insC). The patient received six cycles of paclitaxel plus carboplatin chemotherapy, resulting in a significant reduction of ovarian and breast tumor lesions by more than threefold and stabilization of the gastric tumor as assessed by imaging. Following partial response, radical surgical treatment was performed, including distal subtotal gastrectomy with D2 lymphadenectomy, hysterectomy with bilateral salpingo-oophorectomy, and right mastectomy. Considering the detected BRCA1 mutation, maintenance therapy with the PARP inhibitor olaparib was administered for 24 months in combination with aromatase inhibitors. During two years of follow-up, no disease progression was observed, the therapy was well tolerated, and adverse effects were limited to grade 1 anemia. This case highlights the clinical value of molecular genetic testing and a multidisciplinary approach in patients with MPM. Identification of a germline BRCA1 mutation allowed for selection of an effective systemic therapy, including platinum-based agents and a PARP inhibitor, achieving durable remission in the context of multiple synchronous primary tumors. The report underscores the importance of personalized treatment strategies for patients with synchronous multiple malignancies.

Cutaneous metastasis as the initial presenting sign of an underlying gastric signet ring cell carcinoma (SRCC) is very rare and easily confused with benign dermatologic disease. We present a 46-year-old female who developed multiple firm, erythematous nodules over the breast, shoulder, and buttocks over 3 months. The skin lesions were initially treated as soft-tissue infections, but there was no response to therapy. A core biopsy of the skin ultimately disclosed metastatic adenocarcinoma with prominent intracytoplasmic mucin and signet-ring morphology; similar malignant cells were subsequently identified in pleural and ascitic fluids. Immunohistochemical (IHC) studies demonstrated a CK7-positive, CK20-negative pattern with strong mucin expression and weak CDX2 labeling, consistent with an upper gastrointestinal primary. Cross-sectional imaging identified diffuse gastric wall thickening consistent with lienitis plastica, peritoneal and pleural involvement, and distant osseous metastases. Poorly differentiated signet ring cell gastric adenocarcinoma was confirmed through endoscopic biopsies, defining stage IV disease. Fluoropyrimidine-platinum chemotherapy and then second-line irinotecan failed to halt disease progression in this patient; her cancer reflected the classic chemo resistant behavior for this histologic subtype. She survived approximately two years after diagnosis. This case thus underlines the need to include metastatic cancer in the differential diagnosis of any persisting or atypical skin nodule: an approach which calls for early biopsy and well-thought-out interpretation of immunophenotyping findings, followed by timely integration of imaging to disclose the silent gastric malignancy and guide management appropriately in a multidisciplinary manner.

Background: Less than 1% of all colorectal cancers (CRCs) are primary colorectal signet-ring cell carcinomas (SRCCs), which represent an uncommon and aggressive histological subtype. Given their subtle onset and rapid progression, these are often diagnosed in an advanced stage, and can be distinguished by the presence of mucin-producing signet-ring cells. Synchronous colonic metastases at initial diagnosis are rather uncommon. Case presentation: We report the case of a 65-year-old male patient who underwent a routine colonoscopy following a positive fecal immunochemical test (FIT). The patient had no remarkable medical history and was asymptomatic. A 3 cm semi-pedunculated polyp and several smaller depressed lesions, 2 cm maximum in diameter, were observed in the descending colon during the colonoscopy. Multiple biopsies were obtained. The lesions were found to be SRCC according to histopathological examination. There was no sign of extra-colonic metastases on the computed tomography (CT). The patient was referred for extensive hemicolectomy, regional lymphadenectomy, and adjuvant chemotherapy. Conclusions: This article provides a thorough literature review on this uncommon presentation and discussion regarding the current understanding of the pathogenesis, clinical manifestations, and management strategies of SRCC. This case highlights the importance of routine screening in detecting aggressive malignancies like SRCC in asymptomatic individuals. Early identification through colonoscopy can lead to timely intervention, potentially improving prognosis.

To present a rare case of advanced gastric linitis plastica with malignant ascites and the Bombay (hh) blood group, managed successfully with open Witzel feeding jejunostomy for palliative nutritional support and facilitation of systemic chemotherapy. A 42-year-old female presented with progressive abdominal distension, early satiety, nausea, and weight loss. Clinical evaluation revealed severe malnutrition, ascites, and gastric outlet obstruction. Endoscopy and biopsy confirmed signet ring cell carcinoma (diffuse type). Due to the presence of gross ascites and the rare Bombay blood group, open Witzel feeding jejunostomy was selected over laparoscopic techniques for safe enteral access. The procedure was performed under intravenous sedation via an upper midline laparotomy. The postoperative course was uneventful. Enteral feeding through the jejunostomy tube was initiated on postoperative day one and supplemented with oral feeding by day five. The patient showed improved nutritional tolerance and was started on Capecitabine chemotherapy under palliative intent. No early postoperative or transfusion-related complications were reported. Open Witzel feeding jejunostomy is an effective and safe approach for enteral nutritional support in advanced gastric cancer cases with contraindications to laparoscopy. In patients with rare blood groups such as Bombay (hh), open techniques provide better intraoperative control and transfusion preparedness, supporting individualized surgical decision-making in complex oncologic care.

Signet ring cell carcinoma (SRCC) is a special type of poorly differentiated adenocarcinoma. This study aimed to create a nomogram to predict survival outcomes in SRCC individuals. Joinpoint regression method was used to analyze cancer incidence trends and survival. Cox proportional hazards regression identified independent prognostic factors affecting survival, which were then used to construct the nomogram. The diagnostic accuracy of the model was tested with receiver operating characteristic curves. Clinical utility of the model was validated through decision curve analysis, and predictive accuracy was assessed with calibration curves. Using the Kaplan–Meier curve to evaluate the survival time under the special risk factor. SRCC was most commonly observed in the stomach, followed by the colon and rectum, with a decreasing trend in incidence. Our data came from the Surveillance, Epidemiology, and End Results database, including 10,570 patients who were randomly divided into a training set (n = 7402, 70%) and a validation set (n = 3168, 30%). Cox regression identified age, race/ethnicity, TNM staging, surgery, chemotherapy, and tumor size as independent prognostic factors, which were used to develop the nomogram. In the training group, the nomogram demonstrated strong predictive effectiveness for 1-year, 3-year, and 5-year survival, with areas under the receiver operating characteristic curve of 0.806 (95% confidence interval [CI]: 0.795–0.817), 0.811 (95% CI: 0.801–0.821), and 0.811 (95% CI: 0.800–0.822), respectively. In the validation group, the areas under the receiver operating characteristic curve were 0.810 (95% CI: 0.794–0.826) for 1-year, 0.828 (95% CI: 0.813–0.843) for 3-year, and 0.826 (95% CI: 0.810–0.842) for 5-year. The decision curve analysis confirmed the clinical applicability of the nomogram, and the calibration curves demonstrated strong consistency between predicted and observed survival. This study present a robust predictive model that offers a personalized and simplified approach to forecast survival outcomes in SRCC patients.

Background: Although pathological node-negative (ypN0) status is associated with favorable outcomes in rectal cancer patients, recurrence still occurs. Objective: To compare the clinical stage, tumor biology, treatment response, and survival outcomes between ypN0 young-onset rectal cancer (YORC) and late-onset rectal cancer (LORC) patients and identified factors associated with recurrence. Materials and Methods: The present study was a retrospective cohort study included 159 ypN0 rectal cancer patients treated between 2013 and 2019 at two tertiary centers in Thailand. Patients were categorized into YORC, younger 50 years, and LORC at 50 years or older groups. Clinical and pathological characteristics, treatment response, disease-free survival (DFS), and overall survival (OS) were analyzed. Prognostic factors for recurrence were identified via Cox proportional hazards regression. Results: Among 159 patients, 32 (20.1%) had YORC and 127 (79.9%) had LORC. YORC patients presented a greater prevalence of poorly differentiated, mucinous, and signet-ring cell histology. No significant differences were observed in 5-year DFS (p=0.072) or 5-year OS (p=0.127), although YORC patients demonstrated a trend toward earlier recurrence at 303 versus 406 days. Independent risk factors for recurrence included lateral lymph node involvement (adjusted HR 3.341, p=0.011), positive resection margins (adjusted HR 6.519, p=0.004), and a lower number of harvested lymph nodes with less than 12 (adjusted HR 1.099, p=0.007). Conclusion: There were no statistically significant differences in OS or DFS between ypN0 YORC and LORC patients. However, optimizing lymph node retrieval and positive resection margin remain essential, and closer follow-up may be beneficial for YORC patients given their trend toward earlier recurrence.

Patients undergoing periods of starvation or malnutrition may develop degenerative and/or atrophic changes of various organs. These findings may manifest histologically and may cause confusion when first encountered, raising a differential that includes benign and malignant tumor entities. Herein, we report 16 cases of incidentally identified degenerative changes within abdominal-site fatty tissues that caused diagnostic difficulties. The patients were 11 males and 5 females, aged from 1 day to 82 years (mean: 58years). The degenerative changes were all incidentally identified within adipose tissue of the abdominal cavity or adjacent to organs contained within the abdominal cavity in procedures done for unrelated reasons such as cancer, infection, or perforation. Cases were identified in the colon (n=6), small intestine (n=4), omentum (n=3), inguinal hernia sac (n=1), peritoneum (n=1), and retroperitoneal soft tissue (n=1). Patients had variable past medical histories with multiple comorbidities. Ten patients presented with some form of malnutrition and/or cachexia. Histologically, the lesions demonstrated lobules of atrophic-appearing fat with small signet-ring-like adipocytes that were sometimes bilobed. The nodules varied in size and were characterized in some cases by a variably myxoid stromal background, often with a prominent delicate capillary network. Immunohistochemistry was performed and was uniformly positive for S100 protein and negative for cytokeratins. The lesions were generally recognized as degenerative, but various differential diagnoses proposed at the time of sign-out included signet-ring cell carcinoma, liposarcoma, and vascular lesions, among others. Nomenclature to describe this phenomenon has been inconsistent in the literature, and thus, we suggest the term "pseudoneoplastic fat atrophy."

Breast metastasis from gastric adenocarcinoma is exceptionally rare, with only a small number of cases reported in the literature. These metastases often occur in premenopausal women and commonly involve the signet ring cell subtype, usually presenting as unilateral, left breast lesions. We present the case of a 33-year-old Asian woman with signet ring cell gastric adenocarcinoma who developed bilateral breast metastases. This case illustrates the diagnostic challenges associated with this rare metastasis and highlights the essential role of multimodal imaging and biopsy in confirming the diagnosis. Early recognition of the condition is critical given the poor prognosis and lack of standardized treatment.

Metaplastic alterations of oxyntic mucosa in autoimmune gastritis (AIG) remain under investigation. This study aimed to characterize pyloric gland-like and intestinal metaplasia (IM) in AIG and assess their origin and prognostic significance. A retrospective analysis of 147 H. pylori-negative AIG gastric biopsies was conducted. Twenty cases underwent immunohistochemical staining for MUC5AC, MUC6 and TFF2, and double immunostaining for MUC6-CDX2, MUC5AC-CDX2 and TFF2-CDX2. Corpus mucosa showed pyloric gland-like metaplasia in 98.6% (145/147) and IM in 81.6% (120/147) of cases; IM was complete in 99.2% (119/120). Epithelial dysplasia was absent; one signet-ring cell carcinoma was identified. Most cases were OLGA stage II (92.5%) and OLGIM stage I (58.5%). Metaplastic pyloric-like glands expressed MUC6, the mucin of normal antral glands, but also MUC5AC, the mucin of gastric pits and surface epithelium, a combination congruent with a distinct metaplastic subtype. All cases exhibited biphenotypic gastric mucous cells co-expressing MUC5AC-CDX2 (median 4.8% of MUC5AC-positive cells) and MUC6-CDX2 (median 3.1% of MUC6-positive cells) in glands and surface/foveolar epithelium. Glands with a mixed cellular population showing mucinous, biphenotypic, intestinal and intermediate 'transition' features provided further evidence of intestinal trans-differentiation. TFF2 was present in 25% (5 cases), in few glandular cells without CDX2 co-expression. Oxyntic mucosa metaplasia in AIG constitutes a complex phenomenon of successive phases of cellular plasticity characterized by the appearance of a distinct pyloric-like metaplastic subtype followed by intestinal trans-differentiation. The autoimmune metaplastic background appears non-carcinogenic regarding intestinal-type adenocarcinoma development.

Multiple myeloma with massive proliferation of signet ring cell like plasma cells: a case report

BackgroundAdvanced gastric and colorectal signet ring cell carcinoma (SRCC) exhibit distinct biological behaviors, yet comprehensive characterization of their clinicopathological features, treatment modalities, and survival disparities remains limited. Leveraging the Surveillance, Epidemiology, and End Results (SEER) database, this population-based study aimed to elucidate these critical aspects.MethodsWe retrospectively analyzed 15,214 patients with American Joint Committee on Cancer (AJCC) stage III/IV gastric (n = 10,203) or colorectal (n = 5011) SRCC diagnosed between 2000 and 2021. Clinicopathological characteristics and survival outcomes were compared across cohorts. Four treatment modalities were evaluated: surgery alone, chemotherapy (CT) alone, surgery + CT, and no therapy. Kaplan–Meier analysis and Cox proportional hazards regression were used to assess overall survival (OS) and cancer-specific survival (CSS).ResultsDeclining incidence trends were observed for both malignancies. CT alone was the most frequent treatment in gastric SRCC (39.3%), whereas surgery + CT predominated in colorectal SRCC (47.5%). Colorectal SRCC demonstrated significantly superior OS (HR: 0.62, 95% CI: 0.60–0.65, P < 0.001) and CSS (HR: 0.62, 95% CI: 0.60–0.65, P < 0.001) compared to gastric SRCC across all stratified subgroups. The 5-year OS/CSS rates were 6.3%/7.7% for gastric vs. 18.2%/23.0% for colorectal SRCC. Surgery + CT was associated with improved OS and CSS in both gastric and colorectal cohorts, regardless of AJCC stage III/IV. Multivariate analysis identified age, primary site, stage, treatment, and marital status as independent prognosticators.ConclusionsThis study highlights significant clinicopathological and prognostic heterogeneity between advanced gastric and colorectal SRCC, with colorectal tumors demonstrating more favorable outcomes. Surgery + CT may improve survival, highlighting the need for personalized treatment strategies based on the primary tumor site.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-04263-8.

Abstract Background: Early-onset bowel cancer incidence (age &amp;lt;50 years) has increased worldwide and is highest in Australia, but how trends vary across age, histology, and anatomical site remains unclear. We investigated appendiceal, proximal colon, distal colon, rectal, and anal cancer incidence trends by age and histology in Australia. Methods: Cancer incidence rate data were obtained from nation-wide cancer registries (1990–2020). Birth cohort-specific incidence rate ratios (IRRs) and annual percentage change were estimated using age-period-cohort modelling and joinpoint regression. Findings: Combining all malignant tumour histologies, early-onset incidence rose 5–9% annually, yielding 4,072 excess cases (1.5 per 100,000 person-years; 15% appendix, 28% colon, 48% rectum, 9% anus). Trends varied by site, period, and age: appendiceal cancer rose from 1990–2020 in 30–49-year-olds; colorectal cancers rose from around 1990–2010 in 20–29-year-olds and from 2010–2020 in 30–39-year-olds; anal cancer rose from 1990–2009 in 40–49-year-olds. Across sites, IRRs increased with successive birth cohorts since 1960. Adenocarcinoma incidence in the 1990s versus 1950s cohort was 2–3-fold for colorectum and 7-fold for appendix. The greatest subtype-specific increases occurred for appendiceal mucinous adenocarcinoma, colorectal non-mucinous adenocarcinoma, and anal squamous cell carcinoma. Colorectal neuroendocrine neoplasms, squamous cell carcinomas, and signet ring cell carcinomas rose across early-onset and later-onset strata. Interpretation: Appendiceal, colorectal, and anal cancer incidence is rising in Australia, with variation across age and histology. These generational shifts suggest evolving risk factor profiles and early-life exposures, highlighting the need to identify drivers of this growing burden. Citation Format: Aaron L. Meyers, James G. Dowty, Khalid Mahmood, Finlay A. Macrae, Christophe Rosty, Daniel D. Buchanan, Mark A. Jenkins. Trends in early-onset colorectal, appendiceal, and anal tumour incidence by histological subtype in Australia from 1990 to 2020: A population-based time-series analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr B017.