The Genomic Signatures of Linitis Plastica Signal the Entrance into a New Era: Novel Approaches for Diagnosis and Treatment.

Linitis Plastica (LP) is a rare and aggressive tumor with a distinctive development pattern, leading to the infiltration of the gastric wall, the thickening of the gastric folds and a "leather bottle appearance". LP is an extremely heterogeneous tumor caused by mutations in oncogenic and tumor suppressive genes, as well as molecular pathways, along with mutations in stromal cells and proteins related to tight junctions. Elucidating the molecular background of tumorigenesis and clarifying the correlation between cancerous cells and stromal cells are crucial steps toward discovering novel diagnostic methods, biomarkers and therapeutic targets/agents. Surgery plays a pivotal role in LP management, serving both as a palliative and curative procedure. In this comprehensive review, we aim to present all recent data on the molecular background of LP and the novel approaches to its management.

Primary gastric amyloidosis associated with linitis plastica and delayed progression to systemic amyloidosis and multiple myeloma.

We report the case of a woman in her 50s who underwent, 5 years prior, a total gastrectomy after neoadjuvant chemotherapy for diffuse-type gastric cancer diagnosed during a workup for isolated gastric primary light chain (AL) amyloidosis. At the time of diagnosis, immunoglobulins light chain measurements and bone marrow biopsy were performed to rule out multiple myeloma and came back normal. Three years later, the patient developed systemic amyloidosis involving the heart and the lungs, after which she developed multiple myeloma. Isolated amyloid deposits in the stomach are a rare finding. While AL amyloidosis is frequently found in concomitance with multiple myeloma, late progression of primary AL amyloidosis to systemic amyloidosis and multiple myeloma is uncommon.

Gastric Linitis Plastica: Clinical Characteristics and Outcomes from the National Cancer Database.

BACKGROUND/AIM: Gastric linitis plastica (LP) is a rare type of gastric tumor with limited data. We sought to investigate the clinical characteristics, treatment modalities, and outcomes utilizing a national database. PATIENTS AND METHODS: The National Cancer Database (NCDB) was reviewed for LP of the stomach from 2004 to 2017. Kaplan-Meier analysis and Cox proportional hazards model were utilized to evaluate overall survival and predictors of survival. RESULTS: Out of 222,488 gastric cancer cases, 896 patients with histologically confirmed primary gastric LP were included. Patients were predominantly white (78.5%), female (51.9%) and presented at advanced stage disease (stage 4=69%). A total of 369 (41.2%) patients underwent surgical resection, 520 (58.0%) received chemotherapy and 158 (17.6%) received radiation therapy. The mean OS (overall survival) of the entire cohort was 16.9 months with 1-year and 5-year OS rates of 33% and 5%, respectively. Mean OS for the patients receiving surgery with chemotherapy and/or radiation, surgery alone, chemotherapy and/or radiotherapy alone, and no treatment was 28.4, 17.1, 12.3, and, 8.1 months, respectively (p<0.001). On multivariate cox-regression analysis, advanced-stage disease (stage IV) (p<0.001), no surgical resection (p<0.001), and no receipt of chemotherapy (p<0.001) were associated with increased hazards of death. Over time, the proportion of patients receiving surgical resection (30.7% from 48.3%) and radiation therapy decreased (13.8% from 20.6%) and the use of chemotherapy increased (63.9% from 54.8%). CONCLUSION: Gastric LP is associated with a poor prognosis. Multimodal therapy including surgical resection and systemic therapy in the neoadjuvant setting seems to provide the best long-term outcomes.

Survival benefit of younger gastric cancer patients in China and the United States: A comparative study.

BACKGROUND: The impact of racial and regional disparity on younger patients with gastric cancer (GC) remains unclear. AIM: To investigate the clinicopathological characteristics, prognostic nomogram, and biological analysis of younger GC patients in China and the United States. METHODS: From 2000 to 2018, GC patients aged less than 40 years were enrolled from the China National Cancer Center and the Surveillance Epidemiology and End Results database. Biological analysis was performed based on the Gene Expression Omnibus database. Survival analysis was conducted via Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: A total of 6098 younger GC patients were selected from 2000 to 2018, of which 1159 were enrolled in the China National Cancer Center, and 4939 were collected from the Surveillance Epidemiology and End Results database. Compared with the United States group, younger patients in China revealed better survival outcomes (P < 0.01). For race/ethnicity, younger Chinese cases also enjoyed a better prognosis than that in White and Black datasets (P < 0.01). After stratification by pathological Tumor-Node-Metastasis (pTNM) stage, a survival advantage was observed in China with pathological stage I, III, and IV (all P < 0.01), whereas younger GC patients with stage II showed no difference (P = 0.16). In multivariate analysis, predictors in China involved period of diagnosis, linitis plastica, and pTNM stage, while race, diagnostic period, sex, location, differentiation, linitis plastica, signet ring cell, pTNM stage, surgery, and chemotherapy were confirmed in the United States group. Prognostic nomograms for younger patients were established, with the area under the curve of 0.786 in the China group and of 0.842 in the United States group. Moreover, three gene expression profiles (GSE27342, GSE51105, and GSE38749) were enrolled in further biological analysis, and distinctive molecular characteristics were identified in younger GC patients among different regions. CONCLUSION: Except for younger cases with pTNM stage II, a survival advantage was observed in the China group with pathological stage I, III, and IV compared to the United States group, which might be partly due to differences in surgical approaches and the improvement of the cancer screening in China. The nomogram model provided an insightful and applicable tool to evaluate the prognosis of younger patients in China and the United States. Furthermore, biological analysis of younger patients was performed among different regions, which might partly explain the histopathological behavior and survival disparity in the subpopulations.

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T-cell receptor sequencing.

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi-cancers. IHC using antibodies against CD4, CD8, and PD-L1 demonstrated scant T-cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T-cell clones shared across tumor regions in any of the patients, while over 94% of T-cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi-regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T-cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.

pCLE detects mucosal neoplastic vascular pattern in gastric linitis plastica.

Linitis plastica (LP) is a very aggressive and rare carcinoma with a scirrhous stroma that affects the submucosal and muscular layers of the stomach even without mucosal alterations. Lack of timely diagnosis is a crucial problem related to its prognosis and treatment. In this study, we investigated the LP-associated vascular pattern as a possible means to improve the diagnosis of these patients. During standard endoscopy, mucosal architecture, tortuosity and enlargement of vessels, as well as the presence of vascular leakage and efficiency of the blood flow were assessed in six LP patients using probe-based Confocal Laser Endomicroscopy (pCLE). In all LP patients, we detected abnormal changes in vasculature. The aberrant features of the vascular network were common to all LP patients examined and consisted of vessel enlargement, tortuosity, and leakage associated with the affected submucosal layer. This is the first study to highlight the presence of marked vascularization associated with LP, characterized by the presence of abnormal and non-functional vessels, similar to what is observed in neoplastic tissues. Therefore, the analysis of LP by pCLE may provide a new endoscopic approach and strategy to better define these patients.

Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica.

BACKGROUND: Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of GLP remain undetermined. METHODS: We subjected 10 tumor-normal tissue pairs to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). 10 tumor samples were all GLP which involves 100% of the gastric wall macroscopically. TCGA data were compared to generate the top mutated genes and the overexpressed genes in GLP. RESULTS: Our results reveal that GLP has distinctive genomic and transcriptomic features, dysfunction in the Hippo pathway is likely to be a key step during GLP development. 6 genes were identified as significantly highly mutated genes in GLP, including AOX1, ANKRD36C, CPXM1, PTPN14, RPAP1, and DCDC1). MUC6, as a previously identified gastric cancer driver gene, has a high mutation rate (20%) in GLP. 20% of patients in our GLP cohort had CDH1 mutations, while none had RHOA mutations. GLP exhibits high immunodeficiency and low AMPK pathway activity. Our WTS results showed that 3 PI3K-AKT pathway-related genes (PIK3R2, AKT3, and IGF1) were significantly up-regulated in GLP. Two genes were identified using immunohistochemistry (IHC), IGF2BP3 and MUC16, which specifically expressed in diffuse-type-related gastric cancer cell lines, and its knockdown inhibits PI3K-AKT pathway activity. CONCLUSIONS: We provide the first integrative genomic and transcriptomic profiles of GLP, which may facilitate its diagnosis, prognosis, and treatment.

68 Ga-PSMA-11 PET/CT and PET/MRI in Rectal Linitis Plastica Secondary to Prostate Adenocarcinoma.

ABSTRACT: Primary or secondary rectal linitis plastica is rare. We describe MRI, 68 Ga-PSMA-11 PET/CT, and PET/MRI findings in a case of rectal linitis plastica secondary to prostate adenocarcinoma. In this case, the rectal linitis plastica was the first manifestation of the prostatic adenocarcinoma, and the rectum was the only metastatic site of the prostate adenocarcinoma. The rectal wall showed circumferential thickening with a concentric ring pattern on MRI, and diffuse intense 68 Ga-PSMA-11 uptake on PET/CT and PET/MRI. Familiarity with the imaging findings of rectal linitis plastica secondary to prostate adenocarcinoma may be helpful for recognition of this rare entity.

[Chronic ischemic gastropathy as a simulator of plastic linitis]. / Gastropatía isquémica crónica como simuladora de linitis plástica.

Chronic ischemic gastropathy is a rare entity, being the atheroesclerotic vascular the most prevalent cause. Clinical and endoscopic manifestations are unspecific and may simulate more frequent pathologies. Cardiovascular risk factors allow us to diagnose and treat these patients earlier. We present the case of a patient with chronic ischemic gastropathy that manifested abdominal pain, weight loss and endoscopic findings as a simulator of linitis plastica. The diagnosis was made with an endoscopic block biopsy after two inconclusive biopsies.

La gastropatía isquémica es una entidad rara, cuya etiología más frecuente es la obstrucción al flujo sanguíneo secundaria a aterosclerosis. Sus manifestaciones clínicas y endoscópicas son inespecíficas, pudiendo simular afecciones más prevalentes. La sospecha clínica en pacientes con factores de riesgo cardiovascular permite un diagnóstico precoz y tratamiento adecuado. Presentamos el caso de una paciente con gastropatía isquémica crónica que se manifestó con dolor abdominal, pérdida de peso y hallazgos endoscópicos compatibles con linitis plástica. Se arribó al diagnóstico con una biopsia endoscópica en bloque luego de haber obtenido dos biopsias previas no concluyentes.

Linitis plastica of the rectum secondary to prostate carcinoma.

Linitis plastica is an intramural carcinoma that may occur in any hollow organ. Rectal linitis plastica (RLP) is a morphological variant cancer that may occur as a primary form of cancer or secondary as a metastasis of a primary malignancy. We report the case of a man in his 70s with RLP secondary to prostate carcinoma who was initially suspected to have an obstructing rectal adenocarcinoma. During colonoscopy a segment of cobblestone mucosa was seen in the distal rectum. Subsequent imaging showed enhancement of all wall-layers of the rectum and diffuse retroperitoneal fat infiltration with traction on both ureters. A prostate-specific membrane antigen scan confirmed RLP secondary to a prostate carcinoma mimicking the clinical and radiological signs of an obstructing rectal carcinoma with retroperitoneal fibrosis.This case emphasises the possible pitfalls in the diagnosis of RLP and the importance of advanced imaging techniques, such as MRI, as well as appropriate histological samples. The patient underwent androgen deprivation therapy to which RLP responded well and neither systemic chemotherapy or surgery was necessary.

Emlorák hasüregi áttétei - Egy szokatlan entitás klinikopatológiai jellemzoi.

Case report: A sixty-five-year-old female patient underwent surgery for severe gastrointestinal symptoms, following an alarming CT image. Laparotomy revealed irresectable gastric cancer and peritoneal carcinosis. Palliative gastro-jejunostomy and ileo-descendostomy were performed. The endoscopic diagnosis - linitis plastica - and the intraoperative macroscopic appearance matched and agreed on the histologically presumed shigillocellular carcinoma. Three years following the initial abdominal symptoms, histological samples taken from newly detected cutaneous metastases which developed during oncological palliative treatment verified occult lobular breast carcinoma. Histological revision of the sample taken from abdominal exploration confirmed the latter diagnosis. The hormone receptor positive, human epidermal growth factor receptor-2 negative malignancy showed very good regression for the palliative hormone treatment. Discussion: About ten percent of breast cancer cases are lobular carcinomas, which are more often multicentric, bilateral, occult and have a propensity to metastasize to serous membranes, abdominal and pelvic viscera. Due to the increasing survival of breast cancer patients, the number of abdominal metastases of breast cancer is expected to increase. Histological confirmation is indispensable even in case of advanced abdominal malignancies, especially in the case of an unusual medical history. The currently rare case demonstrates the need for multidisciplinary cooperation in all diagnostic and therapeutic fields of breast cancer.

Rectal linitis plastica as the first presentation of metastatic lobular breast cancer: an endoscopic ultrasound diagnosis.

Gastrointestinal tract is an uncommon site of breast cancer metastasis. Rectal linitis plastica (RLP) is a rare presentation of rectal neoplasia, both primary and secondary, and refers to a diffuse infiltration of the wall by an infiltrating carcinoma. Diagnostic assessment of RLP may be challenging since cross-sectional imaging and endoscopic findings may be nonspecific, and endoscopic biopsies are frequently non-diagnostic due to the submucosal disease localization. Endoscopic ultrasound (EUS) with fine needle biopsy (FNB) is widely used for the diagnostic assessment of sub-epithelial lesions of upper and lower gastrointestinal tract. However, data about the use of EUS in case of rectal linitis plastica are very poor. We present a case of rectal metastasis as the first presentation of lobular breast cancer, presenting as rectal linitis plastica and diagnosed with EUS-FNB.

Endoscopic ultrasound guided fine needle biopsy in patients with suspected gastric linitis plastica.

BACKGROUND: Gastric linitis plastica (GLP) is a diffuse infiltrating type of gastric adenocarcinoma. It is associated with a poor prognosis and a five-year survival of 3-10%. The infiltrating profile of this tumor explains the low yield of the superficial mucosal biospies. The objective of this study was to investigate the role of endoscopic ultrasound-fine needle biopsy (EUS-FNB) in the diagnosis of GLP. METHODS: We performed a retrospective analysis including all patients who had an EUS-FNB, at a tertiary referral center, over the last 3 years. The primary outcome was the sensitivity of EUS-FNB in patients with suspected GLP. RESULTS: Between January 2017 and December 2020, 34 patients had an EUS-FNB for suspected GLP. Ten patients had a diagnostic of GLP. This diagnosis was obtained by EUS-FNB in 90% (9/10) of the cases. Eight patients had at least one previous esophagogastroduodenoscopy (EGD) with negative mucosal biopsies. Gastric EUS-FNB helped diagnose other serious conditions in 47% (16/34) of cases with inconclusive mucosal biopsies. CONCLUSION: Gastric EUS-FNB in patients with suspected GLP and normal endoscopic mucosal biopsies may lead to a positive diagnosis of GLP in 90% of cases without notable adverse events. This technique should be considered as a second step in the setting of suspicion of GLP after inconclusive mucosal biopsies.

Linitis plastica: current prognostic implication of a classic concept.

BACKGROUND: Despite having been described for several centuries linitis plastica's (LP) prognostic implication remain unclear. OBJECTIVE: To analyze the impact of LP on the survival of patients undergoing gastrectomy for gastric adenocarcinoma. METHOD: A single-center retrospective study of cases of LP diagnosed and confirmed by pathological anatomy has been carried out in a third-level center for 5 years. RESULTS: They were grouped into Linitis Plastica (LP), diffuse non-LP carcinomas (DNLP) and other adenocarcinomas (ADC). 199 gastrectomies performed in the same period of time were included in the comparative analysis. With a median follow-up of 54.5 months (95% CI: 37.0-65.0), the median survival of LP was 14 months (95% CI: 9-27) significantly lower (p = 0.002) compared to DNLP 51.5 months (95% CI: 25-70) and the rest of ADC 62 months (95% CI: 43-68). The OS at 1, 3 and 5 years was statistically worse in the LP group (69, 15, 8%) compared to DNLP (82, 54, 44%) and ADC (89, 63, 54%) (p = 0.073, p <0.001, p <0.001). In the multivariate analysis, LP was identified as an independent risk factor for OS with an HR of 3.26 (p = 0.001). CONCLUSIONS: LP is an independent prognostic factor associated with higher mortality in gastric cancer.

ANTECEDENTES: A pesar de haber sido descrita hace varios siglos, sigue sin estar clara la implicación pronóstica de la linitis plástica (LP). OBJETIVO: Analizar el impacto de la LP en la supervivencia de los pacientes intervenidos de gastrectomía por adenocarcinoma gástrico. MÉTODO: Estudio retrospectivo unicéntrico de los casos de LP diagnosticados en nuestro centro durante 5 años. RESULTADOS: Se agruparon en LP, carcinomas difusos no LP (DNLP) y resto de adenocarcinomas (ADC). En el análisis comparativo se incluyeron 199 gastrectomías realizadas en el mismo periodo de tiempo. Con una mediana de seguimiento de 54.5 meses (intervalo de confianza del 95% [IC 95%]: 37.0-65.0), la supervivencia mediana de la LP fue de 14 meses (IC 95%: 9-27), significativamente menor (p = 0.002) que en los DNLP, que fue de 51.5 meses (IC 95%: 25-70), y que en el resto de los ADC, en los que fue de 62 meses (IC 95%: 43-68). La supervivencia global a 1, 3 y 5 años fue estadísticamente peor en el grupo de LP (69, 15 y 8%) comparado con los grupos de DNLP (82, 54 y 44%) y ADC (89, 63 y 54%) (p = 0.073, p < 0.001 y p < 0.001, respectivamente). En el análisis multivariante se identificó la LP como un factor de riesgo independiente de supervivencia (hazard ratio: 3.26; p = 0.001). CONCLUSIONES: La LP es un factor pronóstico independiente asociado a mayor mortalidad por cáncer gástrico.

Usefulness of endoscopic ultrasound for acquiring the pathological diagnosis of gastrointestinal lymphoma.

BACKGROUND AND STUDY AIMS: This study aims to assess the value of endoscopic ultrasound (EUS) for acquiring a pathological diagnosis of gastrointestinal lymphoma (GIL). PATIENTS AND METHODS: We retrospectively reviewed all GIL patients who underwent EUS from November 2011 to July 2020 at Fudan University Shanghai Cancer Center. All patients with pathologically confirmed GIL were included. The characteristics of the lesions were recorded, and the efficacy for acquiring pathologic diagnosis between white light endoscopy (WLE) and EUS was analyzed. RESULTS: In total, 404 patients with GIL who underwent EUS examination were included in this study. GIL was confirmed in 143 cases by after EUS judgment biopsy (AEJ biopsy), 11 cases by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), 293 cases by WLE biopsy, and 10 cases by surgical pathology for repeated negative pathologic results from EUS and WLE. Among all cases, 78.71% (318/404) were T1-T2, whereas 32.18% (130/404) were determined to have multiple lesions in the digestive tract wall. The positive rates of the WLE biopsy and AEJ biopsy of the involved gastric wall were 77.93% (293/376) and 89.38% (143/160), respectively. Twelve cases showed diffuse thickening of the gastric wall, and the total positive rate of EUS was 91.67% but 0% for WLE with this type of GIL. The total positive rate and positive rate during the first examination of EUS were all significantly higher than those of WLE. Moreover, 19.68% of the patients showed negative results during their WLE examination and then received a positive pathologic diagnosis upon EUS examination, but none had the opposite process. CONCLUSIONS: EUS was found to be a better tool for acquiring a pathological diagnosis of GIL than conventional WLE, especially for GIL similar to linitis plastica.