Gastric Dysplasia and Carcinoma

Gastric Dysplasia

• Gastric dysplasia includes intestinal-type (adenomatous, type 1), gastric-type (foveolar, type 2), and combined (hybrid) forms, each with unique mucin expression.
• Gastric dysplasia is categorized into low grade and high grade.
• High-grade dysplasia is synonymous with carcinoma in situ (CIS).
• Gastric biopsies are grouped into negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia (including CIS), intramucosal carcinoma, and invasive carcinoma.
• The risk of invasive carcinoma is low for low-grade dysplasia and considerable for high-grade dysplasia.
• Surgical excision, including gastrectomy, should be considered when dysplasia is found.

Carcinoma

• The pathogenesis of gastric carcinoma (stomach cancer) is intricately linked to environmental factors, which can differ significantly across geographical regions. For instance, certain countries have observed a decrease in the incidence of this disease, while in others, the rates remain alarmingly high, reflecting a complex interplay of dietary habits, socioeconomic status, and healthcare access.
• Additionally, genetic predisposition contributes to the development of gastric carcinoma in a subset of patients. This genetic link is notably indicated by familial aggregation in approximately 10% of cases, suggesting that inherited factors can enhance susceptibility to malignant transformation in gastric tissues.
• The majority of patients diagnosed with gastric cancer are over the age of 50; however, there are rare instances where younger individuals and even children are affected, highlighting the need for awareness and early detection strategies across all age groups.
• The malignant transformation leading to gastric carcinoma primarily initiates from the generative cells of the foveolae, which are glandular structures in the stomach lining. This progression frequently occurs against a backdrop of chronic atrophic gastritis coupled with intestinal metaplasia, a condition where stomach cells are replaced by intestinal-type cells, which can precede the stages of dysplasia, indicative of cellular atypia and cancer risk.
• Clinically, gastric carcinoma is often associated with hypochlorhydria, a condition characterized by low hydrochloric acid production in the stomach, present in 85% to 90% of cases. This reduced acidity can lead to alterations in digestive processes and may facilitate the development of neoplasia.
• A high intragastric pH offers a conducive environment for bacterial growth, particularly Helicobacter pylori, which can reduce dietary nitrate levels to nitrites. This biochemical conversion is critical as it can subsequently lead to the formation of carcinogenic N-nitroso compounds from dietary amines, further exacerbating cancer risk.
• Chronic atrophic gastritis and gastric carcinoma frequently coexist, raising questions about their etiopathogenic link and the associated risk of malignancy. This relationship continues to be a subject of debate among researchers and clinicians.
• Among the various etiological factors linked with gastric carcinoma, Helicobacter pylori stands out as a significant and well-established contributor. The bacterium is strongly implicated in the pathogenesis of gastric mucosal injury, and the development of cancer, particularly the intestinal-type adenocarcinoma, which is the most prevalent subtype of gastric malignancy.
• The diffuse type of gastric carcinoma, on the other hand, does not demonstrate as strong an association with environmental risk factors as its intestinal counterpart. This indicates distinct pathophysiological processes between the two subtypes.
• Other notable factors that may increase the risk of developing gastric carcinoma include the presence of gastric polyps, Ménétrier disease (a condition characterized by enlarged gastric folds), peptic ulcers, and the gastric stump syndrome, which can occur following gastric surgery.
• In younger patients, some incidences of gastric carcinoma develop following treatments such as irradiation and chemotherapy, particularly in contexts where prior malignancies required aggressive intervention.
• Furthermore, a subset of gastric adenocarcinomas has been linked to Epstein-Barr virus (EBV) infection. These tumors typically exhibit a lymphoepithelioma-like histologic appearance, emphasizing the multifactorial nature of gastric carcinogenesis.

WHO Classification of Tumors of the Stomach

• In the WHO Classification of Tumors of the Stomach, the categorization is comprehensive and helps in guiding diagnosis and treatment plans. The classification includes:

  • Epithelial Tumors

    • Premalignant Lesions: These include adenomas (8140/0), and intraepithelial neoplasias classified into low grade (8148/0) and high grade (8148/2), which represent precursor lesions that may progress to invasive cancer.

    • Carcinoma: This category encompasses a variety of adenocarcinomas based on their morphological characteristics, including adenocarcinoma (8140/3), papillary adenocarcinoma (8260/3), tubular adenocarcinoma (8211/3), mucinous adenocarcinoma (8480/3), poorly cohesive carcinoma which includes signet ring cell variants and other subtypes (8490/3), mixed adenocarcinoma (8255/3), adenosquamous carcinoma (8560/3), carcinoma with lymphoid stroma, also known as medullary carcinoma (8512/3), hepatoid adenocarcinoma (8576/3), squamous cell carcinoma (8070/3), and undifferentiated carcinoma (8020/3).

    • Neuroendocrine Neoplasms: This includes neuroendocrine tumors (NET), which are classified further into NET G1 (carcinoid) (8240/3), NET G2 (8249/3), and neuroendocrine carcinoma (NEC) (8246/3). The latter category includes large cell NEC (8013/3), small cell NEC (8041/3), and mixed adenoneuroendocrine carcinoma (8244/3), alongside endocrine cells like serotonin-producing NET (8241/3) and gastrin-producing NET (gastrinoma) (8153/3).

      • NOTE: The numerical codes provide essential information on tumor behavior, where /0 indicates benign tumors; /1 denotes unspecified, borderline, or uncertain behavior; /2 indicates carcinoma in situ and grade III intraepithelial neoplasia; and /3 designates malignant tumors.

  Morphologic Features and Classification

  • This classification system emphasizes the wide variation that exists in the gross appearance of gastric carcinoma. Depending on the stage of the tumor's development and its biological behavior, clinicians may observe various morphological features ranging from prominently visible abdominal masses to subtle lesions.
  • Intermediate stages can manifest between an intraluminal fungating tumor and a more insidious presentation, such as flat, ulcerated, and deeply invasive tumors.
  • The anatomical location of the tumor significantly impacts its growth pattern; tumors located in the fundic area of the stomach are more likely to invade the submucosa and beyond compared to those situated in the pyloric region.
  • Regarding their physical characteristics, gastric tumors may exhibit diverse appearances including fleshy, fibrous, or gelatinous, which can be influenced by the extent of mucin secretion and the accompanying desmoplastic reaction of surrounding tissues.
  • Any area of the stomach can be affected by carcinoma, and it is noteworthy that multiple tumors are observed in approximately 6% of diagnosed cases, necessitating careful examination for multifocal disease.

  Microscopic Features

  • On a microscopic level, the non-neoplastic mucosa adjacent to the carcinoma is frequently thickened, a feature that can be attributed to the production of epidermal growth factor by the tumor cells, which may stimulate adjacent cellular growth.
  • Gastric carcinomas are predominantly classified as adenocarcinomas, characterized by glandular differentiation.
  • According to the Lauren classification, gastric adenocarcinomas are further designated into intestinal type, which represents approximately 53% of cases, and diffuse type, accounting for around 33% of cases.
  • The remainder of gastric cancers falls into mixed or unclassifiable categories, highlighting the complexity and variability of this malignancy.
  • Intestinal-type adenocarcinomas demonstrate a pattern of differentiation that inversely correlates with tumor size; smaller tumors might exhibit higher differentiation while larger tumors tend to be less differentiated.
  • Well-differentiated tumors typically manifest with columnar cells and exhibit mucin secretion, a histological feature that aids in diagnosis.
  • In contrast, poorly differentiated variants of gastric adenocarcinoma display a solid growth pattern and may lack glandular structures.
  • The production of mucin can significantly vary among different tumors, further complicating their classification and treatment planning.
  • Occasionally, scattered endocrine cells can be identified within the tumor stroma, which may contribute to tumor biology and behavior.
  • The stroma surrounding the tumor may be heavily infiltrated by inflammatory cells such as neutrophils or histiocytes, reflecting a desmoplastic response to the neoplastic process.
  • Diffuse-type adenocarcinomas are classically exemplified by conditions such as linitis plastica and signet ring carcinoma, which are characterized by extensive infiltration of gastric wall and significant desmoplasia.
  • This diffuse growth pattern is noted to occur more frequently in younger patients and appears to be on the rise in the United States, which raises alerts regarding shifting epidemiological trends.
  • In cases of pyloric obstruction, the stomach wall can become thickened and rigid, posing additional complications as the muscle appears hypertrophic and segmented, often with characteristic thin, parallel, grayish-white, longitudinal lines that resemble a comblike appearance.
  • Histologically, a diffuse growth of malignant cells is observed microscopically, often associated with extensive fibrosis and inflammatory changes that accompany tumor progression.
  • In many instances, the mucosal layer is less affected than the deeper layers of the gastric wall, which may delay the detection of the malignancy.
  • Glandular formations are rare in diffuse-type carcinomas, with most tumor cells growing either singly or in linear arrays, further complicating histopathological interpretation.
  • Most of the mucin produced is typically found intracytoplasmically within cells, resulting in the classic signet ring cell appearance, a hallmark of poorly differentiated gastric carcinoma.

  Diagnostic Challenges

  • Diagnostic challenges arise as certain gastric cancers may evade detection during microscopic examination due to their inconspicuous nature.
  • The difficulty in identifying tumor cells is compounded by significant inflammatory and desmoplastic reactions occurring in the surrounding tissues, which can obscure the cancerous cells.
  • Moreover, gastric tumors may closely mimic malignant lymphoma, adding another layer of complexity to differential diagnosis.
  • In making a differential diagnosis, it is crucial to consider dysplastic lesions, reactive changes due to inflammation, bizarre epithelial atypia potentially from previous chemotherapy or radiotherapy, radiation-induced atypical changes, and degenerative alterations associated with erosion and regeneration.

  Histochemical and Immunohistochemical Features

  • Histochemical analysis reveals that the secretory product of the majority of gastric adenocarcinomas, particularly those of the intestinal type, is often an acid mucosubstance, which can assist in differentiating these tumors from other gastric lesions.
  • In contrast, diffuse-type adenocarcinomas may secrete mucin that is either acidic or neutral, complicating histological differentiation.
  • Various mucin types can be expressed in gastric carcinomas, including MUC1 (commonly associated with intestinal-type), MUC5AC (linked to diffuse-type), MUC2 (mucinous subtype), and MUC5B (associated with unclassified carcinomas).
  • MUC5AC is frequently found in tumors located in the antrum of the stomach, while MUC2 tends to be preferentially expressed in tumors arising from the cardia, reflecting histological differences based on anatomic location.
  • Immunohistochemical markers CDX2 and HepPar-1 demonstrate presence in about 90% and 80% of gastric adenocarcinomas respectively. Their expression is indicative of a phenotypic switch from gastric to intestinal characteristics, a transition that is crucial for understanding tumor biology.
  • The keratins found in gastric carcinomas are predominantly of the simple epithelial type; however, there are instances where keratins typical of normal squamous epithelia are also observed, indicating heterogeneity in tumor expression.
  • Expression patterns of CK7 and CK20 vary widely among gastric carcinomas, which can have significant implications for diagnosis and management.
  • Immunohistochemical positivity for proteins such as alpha-1 antitrypsin, alpha-1 antichymotrypsin, and alpha-2 macroglobulin is frequently seen in gastric cancers, providing potential diagnostic markers.
  • In addition, reactivity to human chorionic gonadotropin (hCG) can be found in scattered tumor cells, although these tumors generally do not exhibit distinct histological features different from other forms of adenocarcinoma.

  Molecular Genetic Features

  • Distinct molecular pathways characterize the evolution of intestinal-type and diffuse-type gastric carcinoma; understanding these pathways is crucial for developing targeted therapies.
  • The intestinal-type carcinoma typically follows a multistep progression that begins with chronic gastritis leading to intestinal metaplasia, dysplasia, and ultimately invasive carcinoma.
  • Researchers have proposed that an in situ component exists which may give rise to signet ring carcinomas, indicating a unique pathway for this specific phenotype.
  • On the molecular level, diffuse-type carcinoma demonstrates altered expression patterns of genes associated with cellular interactions with the extracellular matrix, affecting tumor behavior and spread.
  • Familial cases of hereditary diffuse gastric cancer have been linked to germline truncating mutations in the E-cadherin (CDH1) gene, providing a hereditary susceptibility that may warrant prophylactic gastrectomy for young affected individuals.

  Additional Genetic Factors

  • Occult intramucosal signet ring adenocarcinoma is often found incidentally in patients undergoing gastrointestinal evaluations, highlighting the importance of thorough examinations.
  • Female carriers of the CDH1 mutation show an increased risk for lobular breast carcinoma, indicating a broader spectrum of cancer susceptibility associated with this genetic alteration.
  • Somatic inactivating mutations of CDH1 or its promoter hypermethylation are observed in up to 50% of sporadic diffuse-type carcinomas, emphasizing its role in mediating regional cancer risk.
  • Moreover, intestinal-type carcinomas reveal microsatellite instability in 15% to 50% of cases, further underlining the genetic complexity underlying gastric cancers.
  • Mutations in the TP53 tumor suppressor gene and elevated levels of hTERT expression are associated with the more aggressive behavior of some gastric cancers.
  • A minority of gastric carcinomas (5% to 15%) exhibit strong membrane expression of HER2, which can be targeted therapeutically, particularly in patients with advanced disease.
  • Another tumor suppressor gene, RUNX3, is implicated in gastric carcinogenesis, where its loss or mutation can facilitate tumor development.
  • Somatic mutations of the APC gene, commonly associated with familial adenomatous polyposis, are found in 4% to 21% of gastric adenocarcinomas, illustrating the genetic underpinnings shared among various gastrointestinal malignancies.

  Other Microscopic Tumor Types

  • In gastric neoplasms, neuroendocrine differentiation occurs and can manifest with distinct morphology and clinical characteristics. Understanding these variations is vital for correct diagnosis and treatment planning.
  • These neoplasms can typically be categorized into specific groups based on their histopathological features:
  • (1) Well-differentiated neuroendocrine tumors (WDNETs), which are typically slow-growing and exhibit clear differentiation.
  • (2) Tumors exhibiting neuroendocrine differentiation features but with atypical morphology, complicating diagnosis.
  • (3) Small cell carcinomas, which present morphological characteristics consistent with other small cell malignancies.
  • (4) Adenocarcinomas that exhibit neuroendocrine differentiation, indicating a more complex tumor phenotype.
  • (5) Adenosquamous and squamous cell carcinomas, which together comprise less than 1% of all gastric carcinomas, representing an unusual and more aggressive tumor type.

  Mucinous, Hepatoid and Lymphoepithelioma-like Carcinomas

  • Mucinous adenocarcinoma is characterized by distinct glandular formations and abundant mucin deposition, which affect tumor behavior and prognosis.
  • The mucin secreted in these tumors is often a unique O-acylated form of sialomucin, which can be detected using immunohistochemical techniques such as MUC2 staining.
  • From a prognostic standpoint, mucinous adenocarcinoma typically has a better outlook than signet ring carcinoma but does not show significantly different survival rates when compared to ordinary adenocarcinoma.
  • Hepatoid adenocarcinoma exhibits both glandular and hepatocellular differentiation and is typically marked by a tubulopapillary pattern, suggesting a possible enteroblastic differentiation pathway.
  • Lymphoepithelioma-like carcinoma represents an undifferentiated type of gastric carcinoma with intense lymphoid infiltration, closely resembling tumors found in the upper respiratory tract, which adds diagnostic complexity.
  • EBV infection is documented in a significant number of cases of lymphoepithelioma-like carcinoma, which may have implications for treatment options.
  • A lymphocyte-rich gastric carcinoma has been discovered, associated with microsatellite instability, exemplifying the genetic heterogeneity in gastric malignancies.

  Sarcomatoid and Acinar Gastric Cancers

  • Sarcomatoid carcinoma, also known as carcinosarcoma, exhibits dual composition, characterized by the presence of both epithelial elements and a sarcoma-like spindle cell component, challenging the standard approaches to surgical and medical treatment.
  • Adenocarcinoma with rhabdoid features is a particularly rare form of gastric cancer, which presents with a solid growth pattern and contains rhabdoid cells that have paranuclear inclusions filled with intermediate filaments, representing an aggressive variant.
  • Gastric carcinoma may also present with osteoclast-like giant cells; these tumors show scattered multinucleated cells that express histiocytic markers, providing insights into their origin and behavior.
  • Acinar cell carcinoma typically arises from metaplastic pancreatic tissue within the gastric environment, suggesting a unique lineage and biological behavior that differs from classical gastric adenocarcinomas.

  Early Detection Methods of Gastric Carcinomas

  • Early detection methods are critical for improving patient outcomes associated with gastric carcinoma. Symptoms often reflect advanced disease, leading to challenges in timely diagnosis.
    • The first indications of gastric carcinoma can include detection of metastases in regional lymph nodes, the liver, or the lungs, highlighting the aggressive nature of the disease.
    • Radiographic examinations can reveal lesions in the stomach, although subtle lesions may go unnoticed until more advanced imaging techniques are employed.
    • Mass screening strategies, along with endoscopic evaluations, cytology, and biopsy procedures, have significantly advanced the ability to identify early-stage cases. These approaches are vital for prompting further investigations and treatment.
    • Direct-vision gastric biopsy techniques and brush cytology have seen improvements over time, enhancing diagnostic accuracy.
    • Nevertheless, false-negative diagnoses remain a concern, particularly with biopsies of diffuse carcinomas, emphasizing the necessity for comprehensive diagnostic protocols.

  Classification of Gastric Carcinomas

  • According to Japanese authors, early gastric carcinoma is specifically defined as a carcinoma that is confined to the mucosa or extends to the submucosa, with the term intramucosal carcinoma referring to those lesions limited strictly to the mucosal layer.

  Metastasis and Survival Rates

  • Metastatic spread of gastric carcinoma is common, particularly finding that distal carcinomas invade adjacent structures such as the duodenum.
  • Lesions arising in the proximal stomach may involve the esophagus, with tumors originating from Barrett's esophagus complicating management due to their indistinct boundaries.
  • Serosal spread is a frequent occurrence, typically more extensive in tumors with a proliferative pattern of growth compared to expanding types, necessitating vigilant monitoring for peritoneal dissemination.
  • Local extension can involve adjacent structures such as the omentum, colon, and pancreas, which further complicates symptomatology and treatment planning.
  • Survival rates show variability, with five-year survival rates following diagnosis ranging from 80% to 95% in certain cohorts, particularly in cases where early detection is achieved.
  • The presence of lymph node metastases and the characteristics of early gastric carcinomas tend to show a pattern of focal invasion, which lies intermediate between well-defined invasive types of carcinoma. Distal carcinomas frequently involve the duodenum and commonly show esophageal invasion, again underlining the need for comprehensive pathological assessment for accurate staging.
  • To enhance detection rates, a comprehensive cleaning or re-staging approach is often employed, particularly during surgical sections utilizing cytokeratin markers to elucidate the extent of disease.

  Treatment, Japanese Ethnicity, and Prognosis

  • The standard treatment regimen for gastric carcinoma typically involves surgical intervention and tumor removal, tailored depending on the specific tumor type and anatomical site of tumor engagement.
  • Notably, the survival rates for gastric carcinoma patients are generally lower than those observed in Japan, where advancements in early detection and treatment protocols have been made.
  • Common surgical interventions might include partial or radical gastrectomy; however, it is essential to note that these procedures do not universally enhance long-term survival outcomes, necessitating ongoing evaluations of treatment efficacy.
  • The overall survival rate for patients diagnosed with gastric carcinoma varies widely, sitting between 4% and 13%, depending on disease stage at presentation and patient socioeconomic factors.
  • Interestingly, individuals of Japanese ethnicity and female patients often show more favorable prognostic indicators compared to other demographics, potentially reflecting genetic or environmental factors unique to these populations.
  • Outcomes tend to be more favorable for distal gastric tumors in contrast to those in the proximal stomach, where the latter are often associated with more advanced disease at the time of diagnosis.
  • Generally, younger patient age at diagnosis correlates with a more negative prognosis, possibly due to more aggressive tumor biology observed in younger cohorts.

  Genetics and Additional Info

  • In terms of genetic factors, smaller tumors and certain patient profiles may serve as predictors for a higher likelihood of developing invasive disease, implicating the role of tumor biology in disease progression.
  • Tumors associated with specific genetic backgrounds tend to exhibit higher percentages of malignant cells, leading to worse clinical outcomes and survival prospects, underscoring the importance of genetic counseling and targeted therapeutic strategies.