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Linitis plastica

Linitis plastica is a rare and aggressive subtype of diffuse gastric , characterized by extensive infiltration of the wall by poorly differentiated tumor cells, often with signet-ring features, resulting in marked thickening, , and rigidity that imparts a "leather-bottle" appearance to the . This form of cancer typically involves the and muscularis layers, sparing the mucosa in early stages, and accounts for approximately 3–19% of all gastric cancers. It is histologically defined by a scirrhous stroma with increased and muscular triggered by poorly cohesive neoplastic cells. Epidemiologically, linitis plastica is associated with a younger age at , a higher in females, and frequent presentation at an advanced stage, often involving more than one-third of the 's surface. While the primary cause is de novo gastric , secondary cases can arise from metastatic spread, particularly from of the breast. Risk factors align with those of gastric cancer generally, including infection. As of 2025, remains challenging due to high false-negative rates (30–36%) on initial endoscopic biopsies, with recent advances emphasizing tools like endoscopic ultrasound-guided for improved accuracy. is poor, with median survival of 5.7–13.8 months and 5-year survival rates around 11% even after resection.

Definition and Characteristics

Etymology and Overview

The term "linitis plastica" originates from word "linitis," referring to microscopic bands of filaments resembling cloth, and the Latin "plastica," meaning inelastic or not pliable. The term was first introduced in 1779 by Lieudaut to describe a scirrhous and rigid type of gastric , and was coined in its modern form by William Brinton in 1854 (or 1859 per some sources), highlighting the condition's hallmark feature of a fibrotic, inelastic that resembles a "leather bottle." Linitis plastica is a rare and aggressive subtype of gastric classified as the diffuse type under the Lauren histological system, comprising approximately 7-10% of all gastric cancers. It is characterized by widespread submucosal infiltration of malignant cells, resulting in marked thickening and rigidity of the gastric wall, often without prominent surface lesions or ulcers that might otherwise suggest . This infiltrative pattern frequently associates with signet-ring cell morphology, contributing to its poor and diagnostic challenges. On gross examination, linitis plastica presents endoscopically with diffusely thickened , reduced distensibility, and a shrunken, contracted that fails to expand normally, classically termed the "leather bottle" appearance and corresponding to Bormann type IV in the macroscopic classification of advanced gastric cancers. Unlike the more localized, exophytic, or ulcerated forms typical of intestinal-type gastric adenocarcinomas, linitis plastica's diffuse spread through the stomach wall evades early detection and emphasizes its distinction as a highly invasive entity.

Pathological Features

Linitis plastica is histologically characterized as a subtype of gastric featuring predominantly signet-ring cell embedded within an abundant scirrhous stroma. The tumor cells, often poorly cohesive, infiltrate the and muscularis propria layers of the wall, frequently sparing the mucosa in early stages and leading to a diffuse, infiltrative growth pattern. Key pathological traits include a pronounced desmoplastic reaction, where the fibrotic —composed largely of types I and III produced by cancer-associated fibroblasts—can constitute up to 90% of the tumor mass, resulting in extensive and rigidity of the gastric wall. Tumor cells exhibit poor glandular formation and frequent intracellular production, displacing the to create the characteristic signet-ring appearance in over 50% of cases for this variant. This accumulation and lack of cohesion distinguish linitis plastica from more organized gastric malignancies, contributing to its aggressive local . According to the 2019 (WHO) classification of digestive system tumors, linitis plastica falls under poorly cohesive carcinomas, a heterogeneous category that includes signet-ring as a predominant subtype, often classified as poorly differentiated due to the discohesive cellular architecture. Diagnostic challenges arise from the submucosal location and fibrotic nature of the tumor, which can lead to false-negative results in 30–70% of cases depending on the method; multiple deep biopsies or advanced are often required to confirm the diagnosis, highlighting the need for targeted pathological evaluation.

Epidemiology and Etiology

Incidence and Demographics

Linitis plastica accounts for 7-10% of all gastric adenocarcinomas globally. Given the varying incidence of gastric cancer, the annual rate for linitis plastica is estimated at approximately 1-2 per 100,000 individuals in high-risk regions such as , where gastric cancer overall remains endemic, while rates are substantially lower—around 0.3-0.6 per 100,000—in low-incidence areas like and . Demographically, linitis plastica exhibits a slight female predominance, contrasting with the male predominance seen in intestinal-type gastric cancers. It also affects younger individuals, with a mean age at diagnosis of 50-60 years, versus over 65 years for most other gastric cancers; this younger onset is particularly pronounced in hereditary cases linked to diffuse gastric cancer syndromes. Geographically, prevalence is highest in and , reflecting the broader endemicity of gastric cancer in these populations. Incidence appears to be rising among younger cohorts worldwide, potentially driven by improved detection and genetic factors, while overall rates remain stable or show slight increases in non-endemic regions, possibly due to enhanced genetic screening for hereditary forms more common in Western countries.

Risk Factors and Genetic Associations

Linitis plastica, a subtype of diffuse gastric cancer, is influenced by several environmental and infectious risk factors. Chronic infection with is a for gastric cancer, including diffuse forms, primarily through inducing persistent and chronic gastritis; however, the association is stronger for intestinal-type cancers via atrophic changes and , whereas for diffuse types like linitis plastica, genetic factors predominate and the mechanistic role of H. pylori is less direct. Eradication of H. pylori has been shown to reduce the incidence of gastric cancer, including diffuse forms, underscoring its etiological role. Lifestyle and dietary factors also play a role, though their associations are generally weaker for diffuse gastric cancers like linitis plastica compared to the intestinal subtype. High-salt diets, particularly those involving salted, smoked, or pickled foods, increase risk by damaging the and promoting carcinogenic processes. elevates the risk, with a stronger effect observed in men, while a family history of gastric cancer independently heightens susceptibility beyond genetic syndromes. These factors contribute to disease development but are less dominant in diffuse than in intestinal-type cancers. Genetic associations are particularly prominent in hereditary diffuse gastric cancer (HDGC) syndrome, primarily driven by germline mutations in the CDH1 gene encoding E-cadherin, a key protein. Carriers of pathogenic CDH1 variants face a substantial lifetime risk of developing diffuse gastric cancer, estimated at 37% to 70% for men and 25% to 83% for women by age 80 years (though recent 2024 studies from North American cohorts suggest lower risks of ~7–10% for advanced disease). Mutations in CTNNA1, which encodes α-E-catenin and interacts with E-cadherin in adherens junctions, have also been implicated in a subset of HDGC cases, conferring elevated risks for diffuse gastric cancer (~50% lifetime for advanced disease), though evidence is emerging. Given these high risks, screening and preventive strategies are critical for at-risk individuals. Prophylactic total gastrectomy is strongly recommended for confirmed CDH1 carriers, typically between ages 20 and 30, to mitigate the near-inevitable progression to invasive cancer. For those opting to delay surgery or with CTNNA1 variants where evidence is emerging, annual endoscopic surveillance with multiple random biopsies is advised starting in the late teens or early twenties, alongside counseling on .

Pathophysiology

Cellular Mechanisms

Linitis plastica, a subtype of diffuse gastric , is characterized by the loss of E-cadherin function, primarily due to or in the CDH1 gene or epigenetic silencing via promoter hypermethylation, which disrupts cell-cell adhesion and enables the diffuse infiltration of tumor cells throughout the gastric wall without forming discrete masses. Recurrent in the RHOA gene, observed in approximately 15–25% of diffuse gastric cancers, further promote invasive behavior by altering cytoskeletal dynamics and cell motility. This adhesion deficit allows neoplastic cells to dissociate from the epithelial layer and invade the and muscularis propria, contributing to the disease's aggressive infiltrative pattern. Tumor cells in linitis plastica predominantly exhibit signet-ring morphology, where intracellular accumulation displaces the to the periphery, a feature driven by mutations in mucin-related genes such as MUC6 (observed in approximately 20% of cases). These cells display a high proliferative index, often associated with frequent somatic mutations in TP53 (common in up to 70% of advanced cases), which impair and , allowing unchecked cell division. Additionally, alterations in the PI3K-AKT pathway, including PIK3CA mutations, promote cell survival and evasion of , while upregulation of angiogenic factors like ANGPTL4 and NOS3 supports vascularization to sustain tumor growth. is less prevalent in linitis plastica compared to intestinal-type gastric cancers, with most cases showing microsatellite stable (MSS) status. The invasive behavior is further facilitated by epithelial-mesenchymal transition (EMT), a process triggered by E-cadherin loss and involving downregulation of epithelial markers and upregulation of mesenchymal ones, such as vimentin and integrins, enabling tumor cells to penetrate the submucosal layers without forming a palpable mass. EMT in linitis plastica is linked to activation of pathways like MAPK and PI3K-AKT, with approximately 40% of cases classified as EMT-positive based on transcriptomic profiles, enhancing motility and metastatic potential. This transition, combined with TP53 dysfunction, underscores the tumor-intrinsic mechanisms driving the relentless submucosal spread characteristic of the disease.

Tumor Microenvironment and Progression

The in linitis plastica is dominated by an intense desmoplastic reaction, characterized by the proliferation of cancer-associated fibroblasts (CAFs) that deposit excessive and components, leading to a rigid, stroma that permeates the . This not only imparts the characteristic "leather bottle" appearance to the but also creates a physical barrier that promotes tumor rigidity and hinders the penetration of therapeutic agents, such as drugs. CAFs further exacerbate this by secreting growth factors like hepatocyte growth factor (HGF) and (FGF), which enhance tumor cell invasion and motility within the dense matrix. Progression of linitis plastica typically begins with early submucosal spread of signet ring cells, rapidly infiltrating the muscularis propria and serosa, often resulting in widespread gastric wall thickening before overt symptoms emerge. The disease advances through peritoneal dissemination as the primary metastatic route, with occurring in up to 80% of cases with distant metastases and frequently leading to due to serosal involvement. metastasis is prevalent, affecting 70-90% of patients at , while hematogenous spread to distant sites like the liver is less common, seen in approximately 10% of advanced cases. Several microenvironmental factors contribute to treatment barriers and aggressive progression, including within the dense , which activates hypoxia-inducible factor-1α (HIF-1α) and promotes anoikis resistance, facilitating peritoneal seeding. Tumor-associated macrophages (), particularly the pro-tumorigenic subtype, infiltrate the and foster an immunosuppressive milieu that supports tumor survival and reduces efficacy. This hypoxic, fibrotic environment collectively diminishes drug delivery and enhances metastatic potential, underscoring the poor response to standard therapies in linitis plastica.

Clinical Presentation

Signs and Symptoms

Linitis plastica typically manifests with nonspecific early symptoms, including vague abdominal discomfort, dyspepsia, , or mild unintentional , which are often attributed to benign gastrointestinal conditions such as . These subtle signs arise due to the tumor's diffuse submucosal infiltration, which minimally disrupts the mucosal surface initially, leading to an insidious onset that frequently delays recognition. In advanced stages, patients commonly experience early , persistent , and , primarily resulting from caused by the progressive stiffening and narrowing of the wall. Significant , often exceeding 10% of body weight over several months, accompanies these symptoms, alongside epigastric pain and anorexia. may develop from occult , presenting as or . The tumor's extensive involvement reduces gastric capacity, causing and a sensation of fullness after consuming small amounts of food, further contributing to nutritional decline. This pattern of late-appearing symptoms, often only when the disease is advanced, can postpone diagnosis by months, as the submucosal growth evades early detection.

Associated Complications

Linitis plastica, a diffuse form of gastric , often leads to significant nutritional complications due to the progressive rigidity and impaired motility of the stomach wall, resulting in reduced food intake and . affects 30-80% of patients with gastric cancer at , manifesting as and depleted prealbumin levels, which exacerbate overall frailty. , characterized by severe weight loss, muscle wasting, and systemic inflammation, is particularly prevalent in advanced cases, contributing to a decline in and increased susceptibility to infections. Electrolyte imbalances, such as and , can arise from chronic and inadequate , further complicating patient management. Metastatic progression in linitis plastica frequently results in malignant due to , where tumor cells disseminate across the peritoneal surface, leading to fluid accumulation and . may occur either from direct intramural tumor infiltration causing poor motility or from extrinsic compression by metastatic deposits, as seen in cases of rectal secondary to signet-ring cell spread. In females, ovarian presents as Krukenberg tumors, bilateral masses composed of mucin-producing signet-ring cells originating from the gastric primary, often detected at advanced stages. Patients with linitis plastica face an elevated risk of stemming from cancer-associated hypercoagulability, akin to Trousseau syndrome, with gastric cancer conferring a 4-7 times higher incidence of compared to the general population. Rare but life-threatening perforations of the gastric wall can develop due to tumor-induced weakening and , occurring in less than 1% of gastric cancer cases and typically presenting as acute .

Diagnosis

Initial Evaluation and Imaging

The initial evaluation of suspected linitis plastica typically begins with a thorough clinical history, emphasizing persistent dyspepsia, early , , and , which often prompt investigation in patients with advanced disease. Family history screening is crucial, as linitis plastica is frequently associated with hereditary diffuse gastric cancer syndromes, such as those involving CDH1 gene mutations, increasing lifetime risk to 37-70% in carriers depending on and family history. may reveal epigastric tenderness or a palpable mass, along with signs of or in cases with peritoneal involvement or . Laboratory tests play a supportive role in the initial workup, often showing due to chronic , from protein loss or , and occasionally elevated tumor markers such as (CEA) or carbohydrate antigen 19-9 (). However, these markers have low (typically 20-40%) for linitis plastica, particularly in the diffuse signet-ring cell subtype, limiting their diagnostic utility but aiding in prognostic assessment when elevated. Non-invasive imaging is essential for visualizing gastric involvement and detecting . Contrast-enhanced computed () of the and is the primary modality, demonstrating circumferential gastric wall thickening greater than 1 cm, loss of fat planes, perigastric stranding, and a nondistensible "leather bottle" appearance; while general for detecting parietal thickening in gastric is around 80-90%, it is lower (approximately 26%) for advanced T3-T4 staging in linitis plastica. () complements for better characterization of , showing hyperintense wall thickening on T2-weighted sequences and diffusion restriction in malignant areas. -computed () using 18F-FDG is valuable for identifying distant metastases, with uptake in nodes or liver lesions, though for the is lower (approximately 70%) due to the hypometabolic nature of signet-ring cells. Despite these tools, imaging limitations include nonspecific findings that may mimic benign conditions like or , potentially leading to diagnostic delays, and variable specificity (75-100%) for staging local invasion.

Endoscopy and

Endoscopic evaluation of the in linitis plastica often reveals a rigid, nondistensible gastric wall that fails to expand with air , resulting in a characteristic "leather bottle" appearance due to diffuse submucosal infiltration. The mucosa may exhibit a subtle reticular or lacy pattern with thickened folds and reduced , though overt ulceration or lesions are typically absent, complicating early recognition. These findings reflect the tumor's propensity for widespread stromal invasion rather than superficial mucosal involvement. Diagnosis relies on tissue sampling, but conventional endoscopic biopsies frequently yield false negatives because the malignancy spares the superficial mucosa and resides in deeper layers amid extensive fibrosis. Multiple biopsies (typically 5–10) from various gastric sites are essential to improve detection, as the infiltrative pattern leads to patchy involvement. Advanced biopsy techniques, such as jumbo forceps or bite-on-bite sampling, enhance diagnostic yield by obtaining larger, deeper samples from the submucosa, achieving around 80-87% accuracy in some series for gastric infiltrating tumors. For cases with negative superficial biopsies, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) targets submucosal lesions or perigastric lymph nodes, providing access to deeper tissues with a reported overall diagnostic accuracy of 82.6%. Using a 19-gauge needle with multiple passes and on-site cytopathologic evaluation, EUS-FNA confirms or signet-ring cell in the majority of indeterminate cases, with a surgical rate of 87.5%. This technique is particularly valuable when wall thickening is noted on prior imaging, though it carries minimal risks such as minor bleeding. The false-negative rate for initial endoscopic biopsies in linitis plastica ranges from 30% to 50%, primarily attributable to desmoplastic reaction and submucosal tumor localization, often necessitating repeat or advanced sampling. Adjunctive methods like chromoendoscopy with staining or narrow-band imaging can enhance visualization of subtle mucosal irregularities and microvascular changes, aiding biopsy site selection in early or equivocal presentations.

Staging and Classification

Linitis plastica, a subtype of gastric , is primarily staged using the tumor-node-metastasis (TNM) system outlined in the 8th edition of the American Joint Committee on Cancer (AJCC) manual. This system evaluates the depth of invasion (T), involvement of regional nodes (N), and presence of distant (M) to assign an overall stage from I to IV. Due to its characteristic diffuse submucosal and muscularis infiltration, linitis plastica commonly presents as a T4 , with T4a indicating serosal invasion and T4b denoting extension to adjacent structures such as the or . N is determined by the number of metastatic regional nodes, with N3 (7 or more nodes) frequently observed in advanced cases. Peritoneal dissemination, classified as M1, is prevalent at diagnosis, often resulting in stage IV and precluding curative intent. Histopathological classification systems further refine the characterization of linitis plastica. In the Lauren classification, it is categorized as the diffuse type, featuring poorly cohesive cells, including signet-ring cells, that lack glandular formation and promote widespread stromal . Macroscopically, linitis plastica aligns with Borrmann type IV advanced gastric cancer, marked by ill-defined, infiltrative growth throughout the gastric wall without a palpable mass, leading to a rigid, leather-bottle-like . Prognostic stratification integrates TNM with histological and molecular features. Signet-ring cell , predominant in many cases, serves as an independent adverse prognostic factor, correlating with reduced overall irrespective of clinical presentation. Molecular subtyping per (TCGA) typically places linitis plastica within the genomically stable subtype, characterized by low chromosomal instability, intact TP53 signaling, and recurrent alterations in CDH1 (encoding E-cadherin) and RHOA, which contribute to invasive behavior and poorer outcomes compared to chromosomally unstable subtypes. Accurate is pivotal for management decisions, particularly in evaluating resectability, as T4 and N3 involvement often renders the tumor unresectable for cure. Peritoneal cytology, typically assessed via following confirmation, detects occult M1 micrometastases in up to 20-30% of clinically localized cases, upstaging the disease and guiding toward palliative approaches.

Management and Treatment

Surgical Approaches

Surgical approaches for linitis plastica, a diffuse subtype of , are primarily considered for patients with localized, non-metastatic disease as determined by preoperative staging, aiming for curative intent where feasible. Indications include total or subtotal with D2 for potentially resectable tumors confined to the without extensive peritoneal involvement, particularly in stage III cases. Palliative resection may also be pursued in select advanced cases to alleviate symptoms such as , though this is less common due to the disease's aggressive biology. Resection presents significant challenges owing to the tumor's infiltrative growth pattern, which often results in ill-defined margins and early peritoneal dissemination, leading to unresectability rates of 30-50% in reported series. Positive margins (R1 resection) occur in up to 33-47% of attempted surgeries, necessitating intraoperative frozen section analysis to assess and extend margins when possible. The frequent nodal and further complicates achieving complete tumor removal, with identified in many cases during exploration. Standard procedures involve total gastrectomy for proximal or extensive involvement, or subtotal gastrectomy for distal tumors, combined with D2 lymphadenectomy to address regional nodal spread. Reconstruction typically employs Roux-en-Y esophagojejunostomy following total gastrectomy to restore gastrointestinal continuity and minimize reflux complications. In select cases with limited peritoneal metastases, (HIPEC) may be integrated after to target residual microscopic disease, though its role remains investigational and is reserved for specialized centers. Outcomes remain guarded, with R0 (complete) resections achieved in only 27-49% of cases depending on inclusion of palliative procedures, and curative resections in approximately 36% of operable patients. ranges from 5-7%, higher than in non-linitis gastric cancers due to the technical demands of extended resections. Median overall survival following is 11-14 months, with 5-year survival rates around 7-15% in resected cohorts.

Chemotherapy and Targeted Therapies

Systemic chemotherapy plays a central role in the management of linitis plastica, a subtype of diffuse characterized by its aggressive biology and frequent chemoresistance. Standard perioperative regimens include FLOT (, leucovorin, , and ), which has demonstrated superior efficacy over older platinum-based triplets in resectable gastric cancer, achieving a pathological complete response rate of approximately 16% overall, though rates are lower in linitis plastica due to its desmoplastic . Similarly, the ECF regimen (epirubicin, , and ) remains a foundational option, particularly in resource-limited settings, with overall response rates in advanced gastric cancer ranging from 20% to 40%, though lower rates are observed in linitis plastica due to its desmoplastic impeding drug penetration. These regimens are administered pre- and postoperatively to improve resectability and reduce recurrence risk. Ongoing trials, such as JCOG2204 comparing FLOT to docetaxel//S-1, are evaluating optimized neoadjuvant regimens for scirrhous types like linitis plastica. Neoadjuvant chemotherapy aims to downstage unresectable tumors in linitis plastica, potentially converting them to surgical candidates, but responses are often suboptimal owing to the dense stromal component that limits therapeutic delivery and fosters resistance. following resection follows similar protocols to consolidate local control, yet pathological response assessment remains challenging in this subtype, with complete responses rare even after intensive . Targeted therapies are increasingly tailored to molecular profiles in linitis plastica, where HER2 overexpression occurs in about 10% of cases, primarily in less diffuse variants; combined with extends survival in these HER2-positive subsets, as evidenced by improved median overall survival in advanced disease. For instability-high (MSI-high) tumors, which comprise a small but actionable subset (approximately 5-10%) of diffuse gastric cancers, anti-PD-1 immunotherapies like offer durable responses in select patients. Emerging claudin-18.2-targeted agents, such as , show promise in clinical trials for CLDN18.2-positive advanced gastric cancers, including diffuse types like linitis plastica, with phase 3 data indicating enhanced when added to first-line . In palliative settings for advanced or metastatic linitis plastica, second-line options include -based regimens or monotherapy/combinations, which provide modest survival benefits and symptom control after progression on initial therapy. , a VEGF receptor-2 inhibitor, is particularly effective when paired with taxanes like , though combinations are alternatives for patients intolerant to taxanes. These approaches prioritize while addressing the disease's inherent resistance.

Prognosis

Survival Rates and Outcomes

Linitis plastica, a diffuse subtype of gastric , is associated with a dismal , with overall survival typically ranging from 6 to 12 months following . Globally, the 5-year hovers between 3% and 10%, reflecting the disease's aggressive biology and frequent presentation at advanced stages. In cases amenable to surgical resection, particularly R0 resections, outcomes improve modestly, with survival extending to 15-17 months and 5-year s reaching 8-13%. These figures underscore the limited efficacy of current interventions against the tumor's infiltrative nature. Survival varies significantly by disease stage at . For early-stage disease (stages I-II), 5-year rates can achieve 20-30%, though such presentations are rare due to the subtle onset of symptoms. In contrast, stage IV disease, characterized by peritoneal or distant metastases, yields 5-year below 5%, with median of only 4-6 months even with palliative intent. Regional disparities in outcomes are notable, largely attributable to differences in screening practices and early detection. 5-year rates are around 10-20% in regions with advanced screening practices, such as and parts of , though overall rates remain low (around 5%) where advanced-stage detection predominates. Patients with linitis plastica endure a high symptom burden, including early , weight , and , which severely impair . Palliative interventions, such as systemic or supportive procedures like gastric stenting, can extend by 2-3 months while alleviating symptoms, though they do not alter the overall poor trajectory.

Factors Influencing

Several tumor-related factors significantly influence the prognosis of linitis plastica, a subtype of diffuse gastric cancer characterized by aggressive infiltration. The presence of signet-ring histology, which is prevalent in up to 80% of linitis plastica cases, is associated with a worse overall compared to non-signet-ring diffuse types, due to its propensity for peritoneal dissemination and resistance to standard therapies. Peritoneal metastasis, which is common in advanced cases, drastically reduces , often limiting median overall to less than 12 months even with , as it promotes rapid progression and complicates surgical . Additionally, the typically low tumor mutation burden (TMB) in linitis plastica, averaging around 3-5 mutations per megabase, correlates with diminished responses to , as fewer neoantigens limit inhibitor efficacy. Patient-specific factors also play a critical role in modulating outcomes. Linitis plastica occurs more frequently in younger patients (under 50 years), who often present with more aggressive disease features such as advanced staging and peritoneal involvement, though age itself does not significantly impact survival. The Eastern Cooperative Oncology Group (ECOG) performance status may limit eligibility for curative interventions in frailer patients, though its direct impact on survival varies across studies. Low serum albumin levels (below 3.5 g/dL), often reflective of malnutrition or chronic inflammation, independently predict inferior survival by impairing immune function and treatment tolerance in gastric cancer patients, including those with linitis plastica. Treatment-related variables offer opportunities to improve prognosis when optimized. Achieving R0 resection—complete removal of all macroscopic and microscopic tumor—extends median survival to 18-24 months in operable cases, compared to 8-10 months with palliative procedures, underscoring the value of multidisciplinary approaches for selected patients. Genetic profiling, particularly for present in about 20% of cases, enables eligibility for targeted therapies like in hereditary diffuse gastric cancer subsets, potentially enhancing outcomes through personalized strategies. Emerging biomarkers and influences are shaping future prognostic assessments. Claudin-18.2 expression, detected in roughly 35-50% of gastric cancers including linitis plastica variants, serves as a positive predictor for novel antibody-drug conjugates like , which have shown improved in clinical trials for advanced disease. As of 2024, has demonstrated benefits in CLDN18.2-positive advanced gastric cancer, potentially applicable to subsets of linitis plastica patients. Furthermore, alterations in the gut post-treatment may influence recurrence risk, as has been implicated in promoting metastatic progression and reducing efficacy in gastric cancer models.

History and Notable Cases

Historical Development

The term "linitis plastica," meaning "leather bottle" in reference to the rigid, thickened appearance of the , was first coined by English physician William Brinton in his 1859 treatise on diseases of the , where he described it as a benign condition characterized by hypertrophic inflammation leading to gastric rigidity. Earlier observations of similar gastric induration date back to the late , with French physician Lieudaut introducing the concept in 1779 to denote a scirrhous, inflexible form of associated with poor outcomes. By the mid-19th century, pathologists recognized the condition's malignant potential, though initial classifications often conflated it with inflammatory disorders due to limited diagnostic tools. In the early , linitis plastica was increasingly identified as a form of scirrhous , a diffusely infiltrating with prominent fibrous , distinguishing it from more localized gastric tumors. This recognition solidified in the 1920s through autopsy studies that highlighted its submucosal spread and poor resectability, shifting views from benign to aggressive malignancy. A pivotal advancement came in with P. Lauren's histopathological classification of gastric carcinomas into intestinal and diffuse types, positioning linitis plastica within the diffuse subtype due to its lack of glandular formation and infiltrative growth pattern. By the 1970s, detailed microscopic analyses established the strong association between linitis plastica and signet-ring cell morphology, where tumor cells exhibit intracellular displacing the , contributing to the desmoplastic reaction and diagnostic challenges. This era saw refinements in the World Health Organization's (WHO) histological frameworks, emphasizing poorly cohesive carcinomas like signet-ring cell variants as key features of diffuse gastric cancers. Modern understanding advanced significantly with the 1998 discovery of germline mutations in the CDH1 gene (encoding E-cadherin) as the cause of hereditary diffuse gastric cancer (HDGC), a familial form often presenting as linitis plastica with early-onset signet-ring cell infiltration. Since the 2000s, improvements in imaging modalities such as endoscopic ultrasound (EUS) and multidetector computed tomography (CT) have enhanced preoperative staging, allowing better delineation of the tumor's extent beyond the mucosa. Post-2010, clinical trials have explored targeted therapies, including anti-HER2 agents for select cases and immunotherapy for microsatellite instability-high subsets, though diffuse types like linitis plastica remain resistant to many standard regimens. Recent genomic studies as of 2023 have further elucidated molecular signatures of linitis plastica, integrating The Cancer Genome Atlas (TCGA) data to highlight pathways for potential targeted interventions. Key milestones include Japan's nationwide gastric programs, initiated in the 1960s with photofluoroscopy and evolving to by the 1980s, which have contributed to a substantial reduction in mortality—up to 67% in screened populations—through early detection of precursor lesions. The WHO's 4th edition classification in 2010 and 5th edition in 2019 further integrated molecular subtypes, such as those from (TCGA) project, emphasizing genomic instability and EBV-associated features in redefining linitis plastica within broader spectra.

Notable Cases and Case Studies

One prominent example of linitis plastica arises in hereditary diffuse gastric cancer (HDGC) syndrome, caused by germline mutations in the CDH1 gene, which predisposes individuals to early-onset diffuse-type gastric cancer often manifesting as linitis plastica. In families with HDGC, prophylactic total gastrectomy is recommended for mutation carriers due to the high lifetime risk of developing invasive cancer, with pathological examination frequently revealing multiple early signet-ring cell carcinomas or in situ lesions indicative of linitis plastica even in asymptomatic individuals. For instance, a multidisciplinary case report described a 28-year-old woman with a CDH1 mutation from an HDGC family who underwent prophylactic gastrectomy, uncovering multifocal early diffuse gastric cancers consistent with linitis plastica histology, highlighting the preventive value of genetic screening and surgery in averting advanced disease. Clinical case studies from the illustrate the challenges and occasional successes in managing advanced linitis plastica, particularly with peritoneal metastases. A 2019 report detailed a patient with gastric cancer peritoneal metastases, including linitis plastica features, who achieved 20-year survival following combined with (HIPEC) using and , demonstrating potential for long-term outcomes in select cases with low tumor burden. Conversely, diagnostic delays are common due to the submucosal growth pattern, leading to stage IV presentations; a 2017 described a patient with linitis plastica initially misdiagnosed as , resulting in advanced disease at discovery via endoscopic ultrasound-guided , underscoring the need for advanced imaging in persistent symptoms. These cases emphasize key lessons for linitis plastica , including the of genetic screening in high-risk families to enable prophylactic interventions that detect and prevent progression from early lesions. Additionally, rare profiled responses to have been noted, such as a 1986 case of a young patient with advanced scirrhous gastric carcinoma (linitis plastica) achieving 36-month symptom remission through combined multi-drug (OK-432, PSK, SPG) and , though modern inhibitors show variable efficacy in diffuse gastric cancers.