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Linitis Plastica


Linitis Plastica

Article Author:
Sarah El-Nakeep
Article Editor:
Anup Kasi
Updated:
11/24/2020 10:58:20 AM
For CME on this topic:
Linitis Plastica CME
PubMed Link:
Linitis Plastica

Introduction

Linitis plastica (LP) term was first introduced to the medical field in 1779 by Lieudaut to describe a scirrhous and rigid type of gastric tissue with a deadly outcome.[1] Then later described in more detail in 1859 by Dr. William Brinton, who thought it was a benign condition of the stomach with unique abnormalities, including macroscopic thickening of the gastric wall and sub-mucosal hypertrophy consisting mainly of connective and muscular tissues. The microscopic appearance consisted of bands of filaments looking like linen and hence the term “linitis.” As a result, if scarce malignant cells in the tissue, it remained debatable for a long time whether this was a benign or a malignant disorder, which was finally determined in 1953 by Dr. Arthur Stout. He stated that it is a cancerous tissue; characterized by the fibrous scar-like tissue, produced in abundant amounts in this disease.[2]

LP, a phenotype of gastric carcinoma, is interchangeably but not accurately termed Borrmann type 4, which occurs in the Asian population.[3] Other interchangeable terms include; Schirrous carcinoma, Lauren carcinoma, or signet cell carcinoma.

Etiology

The etiology of linitis plastica is not fully understood, and a lot of research is done to uncover the exact cause of the disease. Gastric cancer in general and LP as a subcategory are more prevalent in the American and Asian populations, especially in Japan, Korea, and China. This could be related to the type of food, mainly low fiber diet, or the ethnicity of the population.[4][5] 

On the other hand, LP is not associated with H.pylori infection or chronic active gastritis.[6] Genetic factors play an important role, such as the CDH1 gene and the HER2 gene.

Epidemiology

Linitis plastica occurs in 7 to 10% of all primary gastric cancer cases.[7] Its prevalence among all gastric carcinomas ranges from 3 to 19%.[1] The prevalence of diffuse tumors is higher in the young age and the females.[2]

Pathophysiology

The pathophysiology of linitis plastica is still unclear, multiple linkages to various genetic mutations have been hypothesized, but as gastric cancer has risk factors like ethnicity, hereditary, diet factors, etc., these are all incriminated as having a possible role in the induction of cancer.

Secondary LP occurs with various types of cancer as a metastasis from primary cancer, for example, breast cancer, and gastric cancer. Still, in some cases, there are rare reports of the primary lesion arising from the colon or ovarian cancer. Also, metastasis for breast carcinoma recurrence could present as LP. The secondary sites of cancer might be in the colon or other gastrointestinal organs but histologically identifiable. The characteristics of submucosal infiltration along with attenuated rigid lumen, occur more commonly in the rectum and sigmoid colon.[8][9][10][11]

E-cadherin protein was implicated 20 years ago as the cause of the diffuse type of gastric cancer and lobular type of breast cancer. E-cadherin causes tumor suppression, and a mutation in its germine gene CDH1 will limit that effect. Risk of acquiring cancer increases with heterozygous CDH1.[12] This hereditary type of LP tends to run in the family members (first and second-degree relatives), especially below the age of 40 years old. Prophylactic aggressive measures in the carriers of this gene require total gastrectomy according to expert recommendations.[12]

Other associated genes include Human epidermal growth factor-2 HER2 gene upregulation or increased expression of its protein.[13]

Histopathology

Linitis plastica is not considered a separate entity in the staging or classification of gastric cancer; rather, it is taken as just a part of the diffuse infiltrating gastric cancer, but its influence on morbidity and mortality is well established.[14]

“Leather bottle” was a term describing the gross appearance of the stomach, where there is limited distensibility of the gastric volume.[15]

Macroscopic Appearance: Diffuse infiltration of tumorous tissue in the submucosa and muscularis propria layers of the stomach. The gastric wall is markedly rigid and thickened.

Microscopic Appearance: Stromal hypertrophy and hyperplasia with poorly differentiated adenocarcinoma and signet ring cells infiltration hence the term “signet cell carcinoma.”[14][3]

History and Physical

Linitis plastica is mostly asymptomatic till advanced disease; this is attributed to the weak sensitivity of the stomach to the limitation of its volume. The symptomatic cases mostly present with dyspepsia (55%) along with vomiting (33%) associated with regurgitation of food from the esophagus and dysphagia (33%) due to the infiltration of the submucosa and muscle layer with gastric wall stromal thickening, thus causing massive limitation in the stomach distensibility.[16]

Symptoms include pain in the stomach, the feeling of a lump in the epigastrium, and unintentional weight loss.[1]

Evaluation

One of the difficult aspects of diagnosing linitis plastica; is the fact that the disease is infiltrating the submucosa and sparing the mucosa; thus, superficial biopsies taken during diagnostic upper gastrointestinal endoscopy may result inconclusive. Recently the role of endoscopic ultrasound proved to be important in the diagnosis of LP cases, as the ultrasound will determine the submucosal thickening and infiltration along with assessing the regional lymph node size/architecture and infiltration of the adjacent structures.[17]

The accuracy of EUS in LP ranges from 64 to 92% in the diagnosis of the T stage and 50 to 90% in the diagnosis of the N stage.[18]

Types of biopsies used are brush cytology and superficial biopsy in the case of regular upper endoscopy and fine-needle biopsy from the EUS. Fine-needle aspiration/biopsy can be performed from enlarged lymph nodes.[1]

High-resolution computed tomography CT scan with contrast is the gold standard for initial diagnosis to detect deep gastric wall thickening in the submucosa and muscle layer, also to detect peritoneal, liver, and lymph node metastasis, thus staging of the disease, and remove any doubt by eliminating other possible differential diagnoses. Also, it could be helpful in early detection of the disease as false-negative biopsies in LP may reach 30% due to unscathed superficial mucosa in the early stages of the disease. Delayed-phase enhancement after injection of the contrast is diagnostic to LP lesion. MRI could be an alternative, equally efficient diagnostic measure if CT is contraindicated or not feasible.[19][12]

Peritoneal lavage by laparoscopy is diagnostic in the case of peritoneal carcinomatosis. CEA and CA19-9 could be elevated and might help with the prognosis, but they lack sensitivity and specificity for LP in serum, although they might be more beneficial in peritoneal lavage in peritoneal metastasis and lymph node invasion, supporting the role of adjuvant chemotherapy in the treatment.[20]

Treatment / Management

While oncology specialists lean towards the palliative systemic therapy, convinced that most cases are already metastasizing at disease presentation and that surgery is a part of a palliative regimen to only 20% of the patients. However, surgery is still considered the only cure for the disease with absent alternatives, backed by the relatively improved survival.[21]

Gastrectomy with systemic therapy, either radiotherapy or chemotherapy, seems a promising approach in some cases of localized linitis plastica. It is associated with increased overall survival.[3]

Total gastrectomy is considered the only cure for the disease, but this is limited by many factors. Firstly, the eligible patients for total gastrectomy are a minority due to the late stage of the disease at the initial presentation in most cases. Secondly, this is a major operation with a high risk of mortality and morbidity, which may affect survival postoperatively.[1] Thirdly, the malnutrition status that the patients suffer postoperatively, most commonly in the form of anemia, is also a limiting factor.[22]

The guidelines differ from western and eastern countries. In western countries, the preferable course of action is total gastrectomy with D2 lymph node dissection associated with peri or postoperative adjuvant chemotherapy. However, this is different in eastern countries where the preferable standard course is postoperative adjuvant chemotherapy after total gastrectomy.[23] S-1 adjuvant oral plus cisplatin chemotherapy is a standard postoperative regimen in Japan.[24] Personalized medicine is another proposed line of treatment depending on the patient biological markers and staging, where a combination of more than one course of chemotherapy or sequential courses according to the disease progress may yield good results in selected advanced cases.[25]

Differential Diagnosis

The following are some important differentials which should be taken into consideration while making the diagnosis of linitis plastica:

  1. Atrophic gastritis (as this could present with dyspepsia and decreased distensibility along with malnutrition due to destruction of the mucosa and loss of mucosal folds)
  2. Hypertrophic H.pylori chronic gastritis (this may resemble the hypertrophy in mucosal folds that occurs in LP due to submucosal infiltration, but here distensibility will remain intact)
  3. Corrosive gastritis (it will be accompanied by corrosive esophagitis with identification from the history)
  4. Other types of diffuse infiltration as lymphoma, GIST, non-Hodgkins lymphoma, adenocarcinoma, Bormann type 3 and 4 (histopathological differentiation will resolve the issue)
  5. Watermelon stomach with portal hypertension and loss of distensibility from the congestion (accompanied by liver decompensation and signs of portal hypertension)
  6. Post partial gastrectomy loss of gastric volume and distensibility (history of the previous operation is identified)

Surgical Oncology

Median survival after surgical resection is about 16.7 months in comparison to 3.6 months in the case of medical-management only. These are similar survival rates when compared to non-LP adenocarcinoma patients.[26]

During surgical resection; the clear margins and frozen section examination intraoperatively (to determine negative margins) ensure cure and decrease disease recurrence.[21]

Radiation Oncology

Radiation, along with chemotherapy, may be used as an alternative neoadjuvant therapy prior to surgery instead of chemotherapy alone. If gastrectomy is performed upfront, and especially in the setting of positive margins, radiation therapy, along with chemotherapy, could be considered postoperatively.

Pertinent Studies and Ongoing Trials

A randomized clinical trial phase 3 on patients with linitis plastica on biological therapy for diffuse gastric cancer type 4 or large type 3 tumors showed that adjuvant chemotherapy S-1 (standard in Japan) with gastrectomy is no different than neoadjuvant chemotherapy and standard postoperative chemotherapy.[25]

Medical Oncology

Metastasis is one of the most important determinants of survival. The disease tends to locally disseminate in the peritoneum, causing peritoneal carcinomatosis, which indicates rapid disease progression. Lymph node metastasis, rectal and colon metastases, and bone metastasis are common in advanced disease and associated with poor prognosis and failure to surgical cure.[1]

Staging

There is a limited clinical significance of diagnosis linitis plastica as a separate entity and difficulty in including it to the known classification systems, which encouraged some authors to abandon the term altogether. This is helped by the lack of consensus agreement on LP definition due to overlapping with other types of cancers that contain signet ring cells. This is not universally agreed, as others still think that this is a well determinant disease with known risk stratification that yields a benefit to the management of patients by predicting the prognosis of the cases.[2][27]

Although there are numerous classification systems for gastric cancer, there is still no gold standard. Here is an overview of the most used classifications:

  • WHO classification: it mainly depends on describing the microscopic appearance of cancer (which is considered its main limiting property) to the following; papillary, tubular, mucinous, mixed adenocarcinomas, and poorly cohesive (which contains the characteristic signet ring cells).[28]
  • Cancer stromal volume classification: this classification depends on the abundancy of stromal tissue and has medullary, intermediate, and scirrhous types, the last being the most abundant. It is a part of the Japanese classification that shares some of the characteristics of the Bormann type 3 and 4.[29]
  • Bormann classification: it is used mainly in Eastern Asian countries. In this classification, LP is similar to Bormann type 4 with its diffuse infiltrating characteristic and thickened gastric mucosa. It is most common in females and young age; the difference is mainly on the prevalence of infiltration in LP is more in the submucosa, which may cause hypertrophy and folding of the mucosa. It is positioned mainly in the upper gastric body with more than one-third infiltration of the stomach, while in Bormann type 4 it is equally distributed in the mucosa and submucosa and positioned in the antrum.[30]
  • Lauren classification: it is classified according to microscopic appearance and origin into; diffuse (which carries similarity to LP and Bormann type 4), intestinal (with glandular like structure), or mixed and indeterminate types.[2]

As any cancerous tumor, TNM classification applies to know the extent of infiltration locally and systemically, according to AJCC Cancer staging.[31]

Prognosis

Linitis plastica carries a poor prognosis owing to the late stage of metastatic disease at the time of the initial discovery of the disease. This late diagnosis is due to absent clinical manifestations at the early stages of the disease, as the gastric mucosa is mostly spared, rendering the patient asymptomatic until the late stages.[15][12]

Median survival ranges from 5 to 17 months in case of surgical intervention.[3] Five-year survival is very low, ranging from 3 to 10% [32]

Complications

Complications are related to the "leathery bottle stomach, which causes limitation in digestion and absorption of food; this will lead to malnutrition and severe cachexia of the patients. As the disease advances, a surgical bypass may be mandatory to relieve the lack of motility in the rigid wall and obstruction. Metastasis could affect various organs as liver metastasis, peritoneal metastasis, causing ascites, liver cell failure, or biliary obstruction.

Deterrence and Patient Education

Patient education in linitis plastica is very helpful, as most of the cases are diagnosed in the advanced or non-curative stage. The patient's understanding of his condition is crucial, and the various options available for his management should be explained clearly. The option of personalized medicine in advanced cases needs an informed and educated patient, also the nutrition of the patient, either oral or parental with or without the need for surgery, should be discussed to ensure the best outcome. Genetic testing and counseling of the patient's relatives and the potential need for prophylactic surgery needs an informed and understanding patient to discuss the condition with his own family.

Enhancing Healthcare Team Outcomes

Linitis plastica needs the coordination of an interprofessional team of gastroenterologists, oncologists, gastric surgeons, radiologists, pathologists, nutritionists, and endstage nursing care. This team should plan the best strategy for each patient on a one-to-one basis because this disease is uncommon with poor prognosis. Communication with the patient and caregivers is mandatory to help in deciding what is best for the patient.[33]

A good diagnosis starts with the radiologist and gastroenterologist, deciding to refer or formulate a team according to the case. The team will decide the best plan that suits the individual patient. Surgical gastrectomy, either partial or total with a suitable margin, is decided by the surgeon in coordination with the oncologist. Postoperative management by a nutritionist and gastroenterologist to relieve the symptoms and improve the quality of life is advisable. The oncologist decides the best radioactive or chemotherapeutic plan postoperative or as a palliative measure from the beginning to the advanced stages. Nursing care and social workers help the patients in different stages of the disease, especially in the late stages.

The level of evidence for LP management is mainly derived from cohort and case series studies due to the rarity of cases and the individuality of the disease.[16] [Level 3]


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