Linitis plastica

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]

The term “linitis plastica” was first used by Dr. William Brinton, an English physician, in 1854.^[1][2] Development of linitis plastica is the result of genetic mutation in the CDH1 (E-cadherin) gene, that is responsible for intercellular adhesions.^[3] On gross pathology, a thick, rigid, and leather bottle-like stomach wall is a characteristic finding of linitis plastica.^[4] On microscopic histopathological analysis, atypical signet ring cells that diffusely infiltrate the stomach wall, submucosal fibrosis and thickening, and a minimal mucosal involvement are characteristic findings of linitis plastica. Linitis plastica usually affects individuals of the Asian race.^[4] The presence of metastasis is associated with a particularly poor prognosis among patients with linitis plastica. Linitis plastica is associated with a 5-year survival rate of approximately 10-20% in Japan.^[3] Total gastrectomy is recommended for the management of local disease and as a prophylactic surgery in patients with hereditary form of linitis plastica.^[3]

The term “Linitis plastica” was first used by Dr. William Brinton, an English physician, in 1854.^[1]

On gross pathology, a thick, rigid, and leather bottle-like stomach wall is a characteristic finding of linitis plastica.^[4] On microscopic histopathological analysis, atypical signet ring cells that diffusely infiltrate the stomach wall, submucosal fibrosis and thickening, and a minimal mucosal involvement are characteristic findings of linitis plastica. Development of linitis plastica is the result of genetic mutation in the CDH1 (E-cadherin) gene, that is responsible for intercellular adhesions.^[3]

The most common cause of linitis plastica is scirrhous adenocarcinoma. Linitis plastica may be caused by germline mutations in the CDH1 (E-cadherin) gene.^[5][1]

Linitis plastica must be differentiated from other diseases that cause thickening of the gastric wall such as lymphoma, other forms of gastric adenocarcinoma, menetrier’s disease, lymphoid hyperplasia, amyloidosis, and granulomatous diseases.^[3][1]

Hereditary form of diffuse gastric adenocarcinoma (HDGC) is usually first diagnosed before 40 years of age, sometimes even before the age of 25 years.^[3] Females are slightly more affected with linitis plastica than males.^[3]Linitis plastica usually affects individuals of the Asian race, particularly the Japanese.^[4]

Common risk factors in the development of linitis plastica may include Asian race, female gender, and the presence of CDH1 gene mutations.^[6][3]

There is insufficient evidence to recommend routine screening for linitis plastica.

If left untreated, patients with linitis plastica may progress to develop symptoms from decreased peristalsis of the stomach that may include dyspepsia, dysphagia, nausea, vomiting, increased satiety, and regurgitation.^[7][3] Depending upon the stage of linitis plastica at the time of diagnosis, the prognosis may vary. The presence of metastasis is associated with a particularly poor prognosis among patients with linitis plastica. Linitis plastica is associated with a 5-year survival rate of approximately 10-20% in Japan.^[3]

Symptoms of linitis plastica may include dyspepsia, nausea, vomiting, early satiety, loss of appetite, weight loss, abdominal pain/discomfort, and sometimes diarrhea.^[3][4][7] A positive family history of diffuse gastric cancer may be present if it is the hereditary form of the disease.

Common physical examination findings of linitis plastica may include lymphadenopathy, organomegaly, and signs of ascites.^[8][9]

Laboratory findings consistent with the diagnosis of linitis plastica may include abnormal complete blood picture, electrolyte abnormalities, and occult blood in stool.^[9]

There are no electrocardiogram findings associated with linitis plastica.

On CT abdomen, linitis plastica is characterized by diffusely thickened stomach with a small lumen. CT of chest, abdomen and/or pelvis may be performed to detect metastases to lymph nodes or any other organs.^[1]

MRI of chest, abdomen and/or pelvis may be performed to detect local invasion and metastasis from or of linitis plastica to breast, lungs and liver.^[10]

Upper GI series may be helpful in the diagnosis of linitis plastica. Findings on upper GI series suggestive of linitis plastica include inadequately distended stomach with increased rigidity and a narrow stomach lumen, loss of normal mucosal fold pattern, and distorted, thickened or nodular mucosa.^[1]

On upper GI endoscopy, linitis plastica may show superficial ulcers and/or inflammation. On endoscopic ultrasound, abnormal thickening of the stomach wall is a characteristic finding.^[3]

The predominant therapy for linitis plastica is surgical resection. Adjunctive chemotherapy and radiation may be required.^[3]

Total gastrectomy is recommended for the management of local disease. Surgical resection is not recommended among patients with metastatic linitis plastica.^[3]

Effective measure for the primary prevention of hereditary diffuse gastric adenocarcinoma includes prophylactic gastrectomy in individuals who test positive for CDH1 gene mutations.^[11]

There are no secondary preventive measures available for linitis plastica.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Reports on linitis plastica date as far back as the sixteenth and seventeenth century. The term “linitis plastica” meaning leather bottle was first used by Dr. William Brinton, an English physician, in 1854 in reference to the appearance of the stomach’s wall lining.

Dr. Brinton was the first to categorize this cancer as a separate entity to other pathologies. The stomach muscle lining was uncharacteristically thicker than usual. For many years, this type of cancer could not be classified as either benign or malignant. In 1953, Dr. Arthur Stout noted that there were scattered cells among the filamentous bands of scar tissue that were malignant. Dr. Stout then further proposed that this cancer was, in fact, a subset of gastric cancer.^[1]

• Linitis plastica was first discovered by Dr. William Brinton, an English physician, in 1854.^[2]
• In 1953, Dr. Arthur Stout was the first to categorize linitis plastica as malignant.

Napoleon Bonaparte, a French military and political leader is thought to have died from this type of cancer.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

It is thought that linitis plastica is generally a sporadic disease that may be inherited as a result of abnormal molecular pathways (Beta catenin/Wnt signaling) that causes defective intracellular adhesions.

• In diffuse type gastric cancer, the cells experience a loss of expression for cell adhesion protein E-cadherin.^[1]
• The E-cadherin gene (CDH1) codes for a transmembrane cellular adhesion protein that provides a tail that adheres to other cells.
• The tail interacts with catenins in the neighbouring cell and forms a cell to cell complex in what is known as Beta catenin/Wnt signaling.
• The loss of these cellular interactions leads to the formation of cancerous cells that trigger a stromal reaction leading to diffuse schirrous (fibrous) changes.

• Linitis plastica is transmitted in an autosomal dominant pattern in hereditary diffuse gastric cancer.^[2][3][4]
• Genes involved in the pathogenesis of linitis plastica include CDH1 gene, located on chromosome 16q22.1, which codes for the E-cadherin protein.
• The development of linitis plastica is the result of germline truncating mutations spread over several exons.
• Consequently, the second allele coding for E-cadherin is inactivated in a two-hit theoretical manner.
• Mutations include:
  • Promoter hypermethylation
  • Loss of heterozygosity
  • Silencing mutation

• Women with diffuse type gastric cancer are also at an increased risk of lobular breast cancer.
• Susceptibility to diffuse gastric cancer may also be linked to inherited polymorphisms in the PSCA (prostate stem cell antigen) gene, which is possibly involved in regulating gastric epithelial cell proliferation.^[5]

• On gross pathology, a thickened, rigid, and leather-like stomach wall is a characteristic finding of linitis plastica.
• Linitis plastica may appear as plaques of fibrosis, which give the appearance of a segmental infiltration with a lack of distensibility.

On microscopic histopathological analysis, tumor cells are seen invading surrounding tissue, with no glandular formation and abundant mucin that push the nucleus to one side producing what is known as a signet ring cell. Signet ring cells are a characteristic finding of linitis plastica.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Linitis plastica may develop as a primary or secondary pathology. As a primary pathology, linitis plastica may be due to defective intracellular adhesions caused by germline truncations mutation in CDH1 gene. CDH1 gene codes for E-cadherin adhesion protein. Secondarily, linitis plastica may be caused by metastasis to the stomach or by the ingestion of lye.

• Linitis plastica can develop in an autosomal dominant pattern by a mutation in the CDH1 gene.^[1]
• Somatic mutations in the CDH1 gene can occur by:
  • Hypermethylation
  • Loss of heterozygosity
  • Silencing mutations

• Lye ingestion
• Metastatic infiltration of the stomach by:
  • Lung cancer
  • Breast cancer
  • Non-Hodgkin lymphoma^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

Linitis plastica must be differentiated from other diseases that cause thickening of the gastric wall such as other forms of gastric adenocarcinoma, lymphoma, Menetrier’s disease, lymphoid hyperplasia, amyloidosis and granulomatous diseases.

Linitis plastica must be differentiated from other diseases that cause thickening of the gastric wall:^[1][2]

• Malignant diseases:
  • Scirrhous adenocarcinoma
  • Lymphoma
• Benign diseases:
  • Menetrier’s disease
  • Lymphoid hyperplasia
  • Amyloidosis
• Granulomatous diseases:
  • Crohn’s disease
  • Tuberculosis
  • Sarcoidosis
• Gastric scarring; due to corrosive ingestion

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

The exact incidence and prevalence for linitis plastica is unknown, however, linitis plastica is estimated to account for almost 30% of gastric cancers (previously thought to be 10%) with a declining incidence. There is a particularly high incidence rate in those individuals belonging to the Korean, Chinese and Japanese races.

• The exact incidence of linitis plastica is unknown.^[1]
• The incidence for gastric cancer overall in 2012 was 7.2 per 100,000 in the United States.
• Linitis plastica was previously thought to account for 10% of gastric cancer, but now may account for as much as 30% of gastric cancers.
• There has been a gradual decline in the incidence of linitis plastica.

• The exact prevalence of linitis plastica is unknown.^[1]
• The prevalence of gastric cancer is estimated to be 22,220 cases annually.
• The prevalence of linitis plastica is approximately 23.5 per 100,000 in 2011 in the United States.

The number of deaths is 3.2 per 100,000 men and women per year.^[1]

Linitis plastica commonly affects individuals younger than 40 years of age. The median age at diagnosis is between 20 – 25 years.^[1]

Linitis plastica usually affects individuals of Asian origin including Korean, Chinese, Taiwanese and Japanese populations. However, it is becoming more frequent in Europe.^[1]

Linitis plastica affects men and women equally.^[1]

The majority of linitis plastica cases are reported in Asia in countries including China and Japan.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

The most potent risk factor in the development of linitis plastica is the presence of CDH1 gene mutations. Other risk factors include Asian race, male sex, and low dietary fiber.

Common risk factors in the development of linitis plastica may include:^[1][2][3][4]

• Asian race (particularly Japanese)
• Male
• Presence of CDH1 gene mutation
• History of breast cancer

Less common risk factors include:

• Low intake of dietary fiber
• Rarely, H.pylori infection

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Hadeel Maksoud M.D.[2]

There is insufficient evidence to recommend routine screening for linitis plastica. However, for familial cases of inherited diffuse gastric cancer, genetic screening for CDH1 gene mutation is available.

• There is insufficient evidence to recommend routine screening for linitis plastica.^[1]
• However, for familial cases of inherited diffuse gastric cancer genetic screening for CDH1 gene mutation is available.
• Screening for gastric cancers is usually carried out via endoscopic biopsy, however, in the case of linitis plastica, barium study may be more effective than endoscopy. The indistensibility of the gastric wall is detected easily with barium.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]

If left untreated, patients with linitis plastica may progress to develop symptoms from decreased peristalsis of the stomach that may include dyspepsia, dysphagia, nausea, vomiting, increased satiety, and regurgitation.^[1][2] Depending upon the stage of linitis plastica at the time of diagnosis, the prognosis may vary. The presence of metastasis is associated with a particularly poor prognosis among patients with linitis plastica. Linitis plastica is associated with a 5-year survival rate of approximately 10-20% in Japan.^[2]

Patients are usually asymptomatic in the initial stages of the disease. If left untreated, patients with linitis plastica may progress to develop symptoms from decreased peristalsis of the stomach and may include dyspepsia, dysphagia, nausea, vomiting, increased satiety, and regurgitation.^[1][2]

Patients with linitis plastica may progress to develop gastric outlet obstruction from the rigid stomach wall that limits the process of digestion.^[3]

Depending upon the stage of linitis plastica at the time of diagnosis, the prognosis may vary. The presence of metastasis is associated with a particularly poor prognosis among patients with linitis plastica because of the rapid peritoneal and lymphatic spread of the disease. Linitis plastica is associated with a 5-year survival rate of approximately 10-20% in Japan.^[2]

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