Stomach Develops As A Dilation Biology Essay

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The stomach is a mixed exocrine-endocrine organ that digests food and secretes hormones. It is a dilated segment of the digestive tract whose main functions are to continue the digestion of carbohydrates initiated in the mouth, add an acidic fluid to the ingested food, transform it by muscular activity into a viscous mass (chyme) and promote the initial digestion of proteins with the enzyme pepsin. It also produces a gastric lipase that digests triglycerides. The fundus and body are microscopically similar structure so that only three histological distinct regions are recognized. The mucosa and submucosa of the empty stomach have longitudinally directed folds known as rugae, which flatten when the stomach is filled with food. The wall in all regions of the stomach is made up of all four major layers (outer most serosa, muscularis propria, submucosa and the inner most mucosa), the mucosa of the stomach consists of a simple columnar surface epithelium that invaginates into the lamina propria, forming gastric pits. Emptying into the gastric pits are branched, tubular glands characteristic of the stomach region (cardiac, gastric and pyloric).The vascularised lamina propria that surrounds and supports these pits and glands contains smooth muscle fibers and lymphoid cells. Separating the mucosa from the underlying submucosa is a layer of smooth muscle, the muscularis mucosae.

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The epithelium covering the surface and lining the pits is a simple columnar epithelium, these cells secrete and release glycoproteins, lipids and bicarbonate which mix up to form a thick, hydrophobic layer of gel with a pH gradient from almost 1 at the luminal surface to 7 at the epithelial cells. The underlying circulatory bed, which provides bicarbonate ions, nutrients, and oxygen to the mucosal cells, while removing toxic metabolic products also acts as defence mechanism. The rich vasculature also favours the rapid healing of superficial wounds to the mucosa. The mucosa of cardiac and pylorus stomach regions contains tubular glands, usually branched; with coiled secretary portions secrete abundant mucus, as well as lysozyme, an enzyme that attacks bacterial walls.

In the fundus and body, the mucosa's lamina propria is filled with branched, tubular gastric glands, three to seven of which open into the bottom of each gastric pit. Each gastric gland has an isthmus, a neck and a base. The epithelial cells in the glands are not uniform. Along with epithelial cells there are few parietal (oxyntic) cells, chief (zymogenic) cells and various enteroendocrine cells are dispersed in the neck and the base of the glands7.

Gastritis

The classification of gastritis has evolved over the years taking into consideration morphology, topography, epidemiology and endoscopy. A classification based on etiology alone is ideal. Gastritis was considered idiopathic until the discovery of Helicobacter pylori8-10.

In 1954, Palmer ED suggested an extensive classification of gastritis in which he broadly divided gastritis into acute and chronic gastritis, sub classifying chronic gastritis into granulomatous and reactive11.

The classification of chronic gastritis by Whitehead et al in 1972 is one of the most popular classifications for routine use12. It documents mucosal site (antrum or corpus), grade of gastritis, activity and the presence of metaplasia. Activity refers to the infiltration by neutrophils into the epithelium of the gastric pits or the surface. Based on the extent of inflammation within the mucosa, two main types, chronic superficial and chronic atrophic gastritis were considered. Chronic superficial gastritis refers to inflammation limited to the level of the gastric pits and surrounding lamina propria. Atrophic gastritis indicates loss of superficial glands and is subdivided into mild, moderate and severe. The combination of severe atrophic gastritis and metaplasia, when associated with only minimal inflammation, is termed gastric atrophy.

Cheli and Giacosa regarded gastric atrophy as part of the spectrum of chronic atrophic gastritis. They introduced the term chronic interstitial gastritis for full thickness mucosal inflammation without atrophy13.

In 1973, Strickland and Mackay divided gastritis into two topographical groups, Type A and Type B. Type A corresponds to fundal gastritis and is associated with circulating antibodies to parietal cell and hypo or achlorhydria. A subset of these patients develops overt pernicious anemia. Type B gastritis mainly affects the antrum and is also called antral gastritis. Parietal cell antibodies are not present in the serum and it is not associated with autoimmune disease14. Glass and Pitchumoni suggested that the term AB be used to describe mixed antral and corporal gastritis15.

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In 1975, Kekki, Siurala, Sipponen et al. disregarded inflammation and metaplasia and based their classification by grading gastritis solely on the loss of normal glands in each gastric compartment. Chronic gastritis with no loss of glands was termed as superficial gastritis 16.

In 1980, Correa classified gastritis into hypersecretory gastritis, similar to earlier Type B affecting mainly the antrum, autoimmune gastritis, similar to earlier Type A, and environmental gastritis similar to Type AB17.

In 1988, taking into consideration the importance of atrophy and the discovery of H.pylori, Correa modified his classification. He divided gastritis into atrophic and non-atrophic types. Non-atrophic gastritis comprised chronic superficial gastritis and diffuse antral gastritis. Atrophic gastritis comprised diffuse corporal atrophic gastritis and multifocal gastritis with intestinal metaplasia18.

In 1900, Yardley modified Correa's classification; Correa's autoimmune and environmental patterns were replaced by metapalstic atrophic gastritis. A third pattern was chronic nonspecific gastritis comprising several forms of gastritis including those associated with H.pylori 19.

Wyatt and Dixon considered Type A gastritis as gastritis to autoimmune factors and Type B gastritis as predominantly antral in distribution and H.pylori associated. They included Type C for gastritis due to reflux, drugs and chemicals. The specific forms of gastritis like lymphocytic, granulomatous, eosinophilic gastritis are listed separately in all above classifications20.

It was difficult for pathologists to report chronic gastritis consistently and to compare their results because of the variety of grading systems of chronic gastritis. In 1990, a group of predominantly European gastroenterologists and the pathologists presented an elaborate reporting system for gastritis to the 9th World Congress of Gastroenterology in Sydney21. The Sydney system, which has endoscopic and histologic divisions, was widely adopted in Europe. It demonstrated considerable inter observer variations in the diagnosis and grading of gastritis as well as poor correlation between endoscopic and histologic findings and lacked the versatility to categorize reliably distinct nosologic entities such as autoimmune and multifocal atrophic gastritis3, 22.

To reappraise the Sydney system four years after its introduction a group of expert panel of gastrointestinal pathologists from various parts of the world met in 1994 & above system was revised in updated Sydney system with some modifications and a visual analogue scale was formulated. The main principles and grading of the Sydney system were retained. A visual analogue scale was provided to assist in the grading into mild, moderate or marked. They recommend five biopsies to be taken from stomach (two from corpus, two from antrum and one from incisura angularis) to classify and grade gastritis. This classification combines aetiology, topography and morphology in the final conclusion of the diagnosis. The aetiology appears as prefix, topography as core and salient morphological features as suffix3,22,23.

The Sydney System of Classification

MORPHOLOGICAL LIMB

The three basic patterns of gastritis recognized are

Acute gastritis when the dominant inflammatory cells are the neutrophils

Chronic gastritis applies to an increase in mononuclear cells with any concomitant increase in neutrophils being referred to as "activity"

Special forms of gastritis in which the morphological pattern has specific clinical and pathogenic implication e.g., lymphocytic gastritis, eosinophilic gastritis, granulomatous gastritis etc.

TOPOGRAPHICAL LIMB

The core of the Sydney system is the topographical distribution in which three patterns of distribution are seen:

Gastritis restricted to antrum

Gastritis restricted to corpus

Pangastritis

AETIOLOGICAL LIMB

In this limb, the aetiology or the most likely pathogenic association is incorporated into the system. H.pylori appears to be the aetiology of gastritis in as much as 80% of patients 3, 23. Where no aetiology or obvious pathogenic association is present, the term idiopathic is used. The main aetiological factors and pathogenic associations are as follows:

a) H.pylori

b) Idiopathic

c) Autoimmune associated

d) Drug or other gastric irritants

e) Infective (excluding H.pylori)

f) Special forms

• Eosinophilic gastritis

• Lymphocytic gastritis

• Granulomatous gastritis

• Crohn's associated gastritis

• Sarcroid associated gastritis

• Reactive gastritis

• Radiation associated gastritis

• Postgastrectomy associated gastritis

The final classification integrates the three limbs of the system. The standard format is to place the aetiology and pathogenic association as a prefix of the core topography. It is then optional to include any salient morphology as a suffix.

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GRADED VARIABLES OF CHRONIC GASTRITIS

1. H. Pylori Density

For clinical purposes, the most important information is whether Helicobacter is present. Variations in H. pylori density may have a bearing on disease associations and epidemiology24-26.

2. Neutrophil activity

Neutrophil activity is an almost universal phenomenon in H.pylori gastritis3, 22. Biopsy specimens contain neutrophils in virtually all cases of H.pylori positive cases if a sufficient number from both antrum and corpus are examined. Neutrophils may be seen in the lamina propria within the epithelium (particularly in the region of the glandular neck) and within the foveolar lumen, where they may form "pit abscesses/ crypt abscess". The density of intra epithelial neutrophils has been correlated with the extent of mucosal damage and with the intensity of H.pylori infection27,28. Neutrophils are very sensitive indicator of the presence or absence of H.pylori and disappear within days of cure of infection.

3. Chronic Inflammation

The normal number of gastric mucosal mononuclear leukocytes in the lamina propria is viewed as a maximum of 2 to 5 lymphocytes, plasma cells and macrophages per high power (x 400 objective) microscopic field or, by another approach, two or three lymphocytes or plasma cells between foveolae (the area in which chronic inflammatory cells are most found). Plasma cells are sparse or absent from the stomach of healthy persons, so their presence is an especially important indicator of a chronic inflammatory response3,22.

4. Glandular Atrophy

Atrophy of the gastric mucosa is defined as loss of glandular tissue. Atrophy leads to thinning of the mucosa and is a common denominator in all pathological processes, causing severe mucosal damage.

5. Intestinal Metaplasia

Intestinal metaplasia is common in the chronic gastritis of all causes and increases in prevalence with disease duration. Metaplasia can be typed by using mucin histochemistry into three main types according to its morphology and glycoprotein content29,30. In type I (which corresponds to complete metaplasia) goblet cells containing sialomucins are interspersed between non-secretory absorptive cells with well-delineated brush borders. In type II, sialomucin-containing goblet cells are scattered among gastric type cells containing either mucin or sialomucins. Type III is characterized by tortuous and branched crypts lined by tall columnar cells containing abundant sulfomucins with smaller numbers of goblet cells containing either sialomucins or sulfomucins. Sulfomucins are differentiated from sialomucins by staining with high iron diamine (HID)/AB using appropriate concentration of ferric chloride and carefully controlled conditions31.

6. Lymphoid Follicles

Lymphoid aggregates with germinal centres are characteristics of chronic H.pylori gastritis and a hallmark of this diagnosis. They are found in 100% of H.pylori positive cases32,33. Lymphoid follicles in a Helicobacter- negative case suggest that the organism have been missed (either overlooked or not present because of sampling errors) or that the infection has been cleared34. In presence of large, irregularly shaped lymphoid follicles or dense population of lymphocytes occupying large portions of the mucosa, the possibility of a mucosa-associated lymphoid tissue (MALT) lymphoma should be considered35,36.

NON GRADEAble VARIABLES

1. Foveolar Hyperplasia

This condition is recognized by increased length and tortuosity of the foveolae combined with expansion of the proliferative compartment and an increase in nuclear size relative to the mucin depleted cytoplasm. It arises either as a compensatory response to increase in cytokines stimulation or growth factor alpha37.

2. Pancreatic (Acinar) Metaplasia

Pancreatic acinar-like cells are characterized by abundant, acidophilic, finely granular cytoplasm in the apical and middle portions and basophilic cytoplasm in the basal compartment. Cells arranged in nests or lobules among gastric glands have been found in 1 to 2% of gastric biopsy and resected specimens38. The presence of pancreatic metaplasia is associated with intestinal metaplasia and chronic gastritis; its significance however remains unclear.

3. Endocrine Cell Hyperplasia

An increase in the number of endocrine cells is most prominent in autoimmune atrophic gastritis. The hypochlorhydria or achlorhydria in that condition leads to G-cell hyperplasia in the antral mucosa and an accompanying rise in circulating gastrin39. The histamine producing enterochromaffin like cells (ECL) are exposed to high gastrin secretions, latter these cells undergo hyperplasia. In a small proportion of patients with autoimmune gastritis, the ECL cell hyperplasia progresses to carcinoid tumour41-44.

4. Chemical or Reactive Gastritis

The diagnosis of chemical or reactive gastritis is indicated by the finding of foveolar hyperplasia, edema, and smooth muscle proliferation in the lamina propria, together with only normal numbers or a minor increase in chronic inflammatory cells. Unless there is erosion, neutrophilic polymorphonuclear cells are not seen. This histological picture suggests an etiological role of some chemical irritant or drugs, in patients who has undergone a partial gastrectomy with gastroenteric anastomosis and bile reflux45-48. Thus, the clinical information might point to a bile-associated chemical gastritis (bile reflux gastritis), whereas a history of NSAID use would indicate an NSAID-associated chemical gastritis. In some patients with reactive gastritis alcohol is the cause, but in most no cause can be identified 47.

5. Lymphocytic Gastritis

Lymphocytic Gastritis is characterized by the presence of large numbers of mature lymphocytes infiltrating the surface and foveolar epithelium49. The increase in intraepithelial lymphocytes can be associated with marked chronic inflammatory cell infiltration of the lamina propria. The histological picture is readily distinguished from ordinary H.pylori associated chronic gastritis. In the latter, one finds four to seven lymphocytes per 100 epithelial cells, whereas ten times this number can be found in lymphocytic gastritis50. Most cases have counts between 25 and 40 lymphocytes per 100 epithelial cells, the diagnostic threshold for lymphocytic gastritis being generally taken as being greater than 25 intraepithelial lymphocytes (IELs) per 100 cells. The IELs are almost exclusively T-lymphocytes and the greater majority (around 90%) is CD8+suppressor cells. This condition is frequently associated with, the endoscopic entity varioliform gastritis, which is characterized by nodular and eroded lesions running along the gastric rugae in the corpus49-51. In some cases the endoscopic and histological appearances overlap with those of Menetrier's disease52,53.

6.Granulomatous gastritis

Granulomas may be present in the gastric mucosa in Crohn's disease, Sarcoidosis, variety of infectious diseases (such as tuberculosis, histoplasmosis) and as reactions to endogenous and foreign materials55-57.

7. Eosinophilic gastritis

Eosinophilic gastritis is a rare condition that is thought to be one manifestation of a generalized involvement of the alimentary tract by an allergic reaction. A marked increase in eosinophils usually focal can be seen in some cases of Crohn's disease & parasitic disease57.

8. Collagenous gastritis

It is characterized by a thick band of collagen immediately beneath the surface epithelium of gastric mucosa58.

9. Infectious gastritis

In patients with disseminated tuberculosis necrotizing granulomas identical to those found in other locations may be found in the gastric mucosa59,60. Staining for acid-fast bacilli reveals large numbers of microorganisms both within the histiocytes and extracellularly in the stroma61. The only viral infection of stomach with a distinct pathologic appearance is that caused by cytomegalovirus (CMV). CMV gastritis is seen almost exclusively in children and immune compromised patients. Usually it is associated with concurrent CMV infection of other sites of the digestive tract. Endoscopically, the gastric mucosa may appear completely normal or show erosions or shallow ulcers. Rarely it might present as a grossly nodular mucosa that has been referred to as a psuedotumor62. In some patients, particularly those with very low CD4 counts, numerous CMV inclusions may be seen in epithelial and endothelial cells as well as in macrophages with little or no inflammatory response in the adjacent tissues. Candida species, Histoplasma capsulatum and Mucoraceae have been found in the stomach of immunocompromised subjects particularly in AIDS patients with disseminated infections63. Cryptosporidium species has been found lining the gastric mucosa, which was virtually free of inflammation64. Several case of giardiasis has been reported55,65.

10. Vascular gastropathies

The only condition that can be confidently diagnosed by histopathological examination of biopsy specimen is gastric antral vascular ectasia (watermelon stomach), a syndrome associated with gastric atrophy, autoimmune and connective tissue disorders62,66. It is histologically characterized by expansion of the mucosa due to fibro vascular hyperplasia and dilated mucosal capillaries67.

Gastric carcinoma

History of gastric carcinoma

Verse was the first to describe early gastric cancer of the stomach as an entity in the year 1903. He reported seven cases of schleimhautecarcinome with carcinoma involving the mucosa and submucosa. Subsequently, such a tumor has been reported variously as carcinoma in situ, carcinoma of superficial spreading type, superficial carcinoma, superficial erosive cancer and surface carcinoma. It was not until 1962 that the concept of early gastric cancer was firmly established when the macroscopic classification of early gastric cancer was presented by the Japanese Gastroenterological Endoscopy Society. Since then combined meetings of clinicians and pathologists have made remarkable progress in diagnostic methods for early gastric cancer, especially in radiologic and endoscopic studies based on morphologic features68.

The 1960s proved to be important in the history of upper gastrointestinal neoplasms. The other change of events in the late 1960s was disregarding the idea proposed by Stout in the 1940s, according to which stromal tumors of the gastrointestinal tract were solely of smooth muscle origin. With the introduction of immunohistochemistry in the early 1980s, it was also soon appreciated that many of these lesions lacked the immunophenotype features of smooth muscle differentiation, and this led Mazur and Clark in 1983 to introduce the more generic designation "stromal tumor".

It was in the year 1984 that Schaldenbrand and Appelman applied the term "stromal tumor" to refer collectively to a group of mesenchymal neoplasms referred to by several names pertaining to neurogenic or myogenic differentiation. Most of these tumors demonstrated some features typical of smooth muscle differentiation, and had been referred to as leiomyomas or leiomyosarcomas. Gradually the term gastrointestinal stromal tumor (GIST) came into widespread use, reflecting both uncertainty over histogenesis of this tumor and the difficulties sometimes associated with predicting the probability of malignant behaviour. Now it is known that the cell of GIST demonstrate immunohistochemical characteristics similar to those of interstitial cells of Cajal or "pacemaker cells"69.

The early detection of different tumors of the upper gastrointestinal tract by endoscopy and assisted biopsy has remarkably improved the prognosis of the patients. Although endoscopic examination of interior of bowel was first recorded by Bozzini in 1807, Kussamaul was the first to successfully study the interior of the stomach employing a 13 mm diameter hollow metal tube. Mickulicz-Radecki in 1881 employed the new electric incandescent lamp as a source of illumination and successfully examined the stomach through the rigid hollow tube, while Mackanzie in 1881 and later Von Hacker in 1904 devised efficient rigid esophagoscopes.

The era of gastrointestinal endoscopy began in 1957 when Hirschowitz and Lawrence Curtis at the University of Michigan developed the first fiberoptic gastroscope70. The technical advances that made the fiberoptic instrument possible began in 1927 when Baird proposed the idea of transmitting light along a flexible axis71.Modern gastroscopy began in 1936 with the introduction by Wolf, an instrument technician, and Schindler, a gastroenterologist of a semi-flexible, efficient gastroscope based on short focal length lenses and prisms72. American Gastroenterologist John Morrissey along with Japanese developed an endoscope that could be passed into the duodenum, and the diagnosis of duodenal ulcer became practical73. In 1950, Uji et al at Tokyo University Hospital developed the gastro camera allowing intragastric photographs to be taken by a distal miniature camera mounted on a flexible tube. Over the next 15years, various Japanese workers adopted this instrument, which incorporated a coherent viewing bundle. The photographs obtained can be subsequently projected or enlarged74.

By 1958 fiber-optic endoscopes were designed, so that now the entire GIT can be examined endoscopically and flexible biopsy forceps were introduced so that a "target biopsy" can also be taken. To this facility brush cytology was added so that current fiberoptic endoscopes can now provide a tissue diagnosis in addition to visual impression. In addition to this, in 1948, Segal and Watson described a practical method of colour photography using rather complicated equipment, the principles of which were adapted a little later by Nelson et al to make a simplified apparatus for the routine recording of gastroscopic findings75.

WHO histologic classification of stomach(76)

Epithelial tumors

Non epithelial tumors

1. Intraepithelial neoplasia-adenoma

2. Carcinoma

• Adenocarcinoma

Intestinal type

Diffuse type

• Papillary adenocarcinoma

• Tubular adenocarcinoma

• Mucinous adenocarcinoma

• Signet-ring cell carcinoma

• Adenosquamous

carcinoma

• Squamous cell carcinoma

• Small cell carcinoma

• Undifferentiated

carcinoma

• Others

3. Carcinoid (well differentiated

neuroendocrine neoplasm)

1. Leiomyoma

2. Schwannoma

3. Granular cell tumor

4. Glomus cell tumor

5. Leiomyosarcoma

6. Gastrointestinal stromal tumor

(GIST)

• Benign

• Uncertain malignant potential

• Malignant

7. Others

8. Malignant Lymphoma

• Marginal zone B cell

Lymphoma of MALT type

• Mantle cell lymphoma

• Diffuse large B cell

lymphoma

• Others

Secondary tumors

INTRAEPITHELIAL NEOPLASIA-ADENOMAS 76

By definition, an adenoma contains dysplastic proliferative epithelium and

thereby has malignant potential. Gastric adenomas are usually antral in locate, it could be single and large, either sessile or pedunculated. Most gastric adenomas have an exophytic pattern. Microscopically, they are composed of dysplastic glands with pseudostratified epithelium showing nuclear abnormalities and high mitotic count. They are further subdivided into gastric type and intestinal type. They can also be subdivided into tubular adenomas, tubulovillous/tubulopapillary and villous adenomas. The risk of malignancy in gastric adenomas is related to their size, degree of dysplasia and villosity of the pattern of growth.

ADENOCARCINOMA

During the last century, a variety of classifications have been proposed for gastric carcinomas by various authors4. These can be listed out as follows:

I. Bormann, 1926

• Type I (polypoid)

• Type II (Fungating)

• Type III (ulcerated)

• Type IV (infiltrative)

V. Japanese Society for Gastric Cancer, 1981

• Papillary

• Tubular

• Poorly differentiated

• Mucinous

• Signet ring

II. Stout (Atlas of tumor Pathology),

1953

• Fungating

• Penetrating

• Spreading

• Superficial spreading

• Linitis plastica

• No special type

VI. World Health Organization, 2000

• Adenocarcinoma

Intestinal type

Diffuse type

• Papillary adenocarcinoma

• Tubular adenocarcinoma

• Mucinous adenocarcinoma

• Signet-ring cell adenocarcinoma

• Adenosquamous carcinoma

• Small cell carcinoma

• Undifferentiated carcinoma

• Others

III. Lauren, 1965

• Intestinal

• Diffuse

IV. Ming, 1977

• Expanding

• Infiltrative

ADVANCED GASTRIC CARCINOMA

Advanced gastric cancer can present grossly as polypoid, fungating,

ulcerated or diffusely infiltrating (linitis plastica) forms. It can present either in one of the above forms or may show a combination of these. Ulcerated tumors occur in the antrum on the lesser curve, they have irregular contours and raised, rolled edges. The polypoid and fungating types are common in the corpus, often the greater curve. The diffusely infiltrating type often presents with conspicuous thickening of the wall, or sometimes the entire stomach known as leather bottle stomach3,4,76.

Microscopically they may have tubular, acinar or papillary structures or poorly cohesive single cells that are widely infiltrative and dissect through the layers of the gastric wall. The tumor cells usually produce mucus, which is positively stained by diastase-PAS or alcian blue. The various classifications for gastric carcinoma have been listed previously. One of the widely used classifications is the Lauren classification, which is important in delineating two different tumor types- the intestinal type and the diffuse type. The intestinal type is strongly associated with chronic gastritis and intestinal metaplasia and epidemiologically more closely linked to environmental factors. It is also known that the geographic differences in gastric cancer incidence are largely due to variations in intestinal type of cancers. The patterns of spread of these two types of tumors are also different; with distal blood borne spread being more common with intestinal-type of carcinomas and widespread peritoneal dissemination being more common with diffuse type of gastric carcinomas3,4,76.

At the immunohistochemical level the main mucin types expressed are MUC 1 for the intestinal type and MUC5AC for the diffuse type and MUC2 for the mucinous type. Among the other immunomarkers, reactivity of gastric carcinomas for cytokeratin (CKs, especially low molecular weight keratins), epithelial membrane antigen and CEA is the rule. Among the cytokeratins, adenocarcinomas of the foregut have a CK 7+/CK 20- expression. The well-differentiated and moderately differentiated carcinomas are positive for several cytokeratins while mucinous carcinomas are associated with CK20 expression. CK6 expression was associated with microsatellite instability 3,76 .

"Early" Gastric Carcinoma

"Early" gastric carcinoma is defined as a carcinoma confined to the mucosa or to

the mucosa and submucosa (not extending into the muscularis externa"), regardless of the status of regional lymph nodes. The other terms that have been used for this are surface, superficial, superficial spreading, and microinvasive cancer. They have been further subdivided into minute and small, depending on the size (less than or equal to 5 mm or 6 to 10 mm in greatest diameter, respectively)4. Intramucosal carcinoma is the type of superficial carcinoma which is limited to the mucosa. This particular variant needs to be differentiated from dysplasia-CIS, which does not show invasion through the basement membrane4,76.

PAPILLARY ADENOCARCINOMA

This is characterized by the presence of numerous papillary processes with

fibrovascular cores.

TUBULAR ADENOCARCINOMA

It is composed predominantly of neoplastic tubules often showing irregular

branching and anastomosis.

MUCINOUS ADENOCARCINOMA

Syn: colloid or mucoid carcinoma. It is characterized by the presence of conspicuous amounts of extracellular mucin (more than 50% of the tumor).

SIGNET-RING CELL CARCINOMA76

It is a diffusely infiltrating carcinoma, accompanied by marked fibrosis, giving

rise to linitis plastica appearance. It consists of predominantly single cells or small

clusters of cells containing intracytoplasmic vacuoles and accounting for more than 50% of the tumor.

SQUAMOUS CELL CARCINOMA76

Pure gastric squamous cell carcinomas are said to be extremely rare, and careful histologic sampling often reveals a glandular component. The occurrence of a pure squamous cell carcinoma in the cardia, more often represents spread from an oesophageal primary, rather than being a primary squamous cell carcinoma of the cardia.`

SMALL CELL CARCINOMA76

It comprises less than 1% of all gastric tumors. Microscopically, it shows sheets or solid nests of small to intermediate-sized, round to spindle-shaped, tumor cells with scanty cytoplasm and fairly regular nuclei, which are hyperchromatic with inconspicuous nucleoli. Mitotic activity is conspicuous. The prognosis of small cell carcinoma is said to be poor with a mean survival of less than 1 year.

GASTRIC CARCINOID TUMORS

The term carcinoid is derived from the word karzinoide meaning "carcinoma like". It was first coined by Siegfried Oberndorfer in 190777. These tumors comprise less than 1% of the neoplasms of the stomach and are commonly associated with chronic atrophic gastritis. They present as small, smooth, firm, well-circumscribed, polypoid elevations of the mucosa and submucosa with a yellow-gray cut surface. Microscopically the tumor cells are arranged in nests and trabeculae, and rarely in acini, rosettes and tubules. The cells are small, uniform with finely granular eosinophilic cytoplasm and regular round to oval nuclei with stippled chromatin, rare mitoses and minimal nuclear pleomorphism. Most of the carcinoids are argyrophilic, while only a few are argentaffin positive. Immunocytochemically they are positive for neuron-specific enolase, chromogranin, synaptophysin, and carcinoembryonic antigen78.

Ultrastructurally, dense core secretory granules are found in the cytoplasm in

abundance. Some carcinoids can present with cytologic atypia in the form of nuclear pleomorphism and hyperchromasia with prominent nucleoli, a more infiltrative growth pattern with obvious vascular invasion and areas of necrosis. There are more than 2 mitotic figures per 10 high-power fields. These carcinoids are called "atypical

carcinoids". Rarely carcinoids, with atypical features can co-exist with adenocarcinomas, so-called composite tumors, adenocarcinoids or carcinoid adenocarcinomas. Based on their pathologic features, gastric carcinoids can be classified into benign, borderline, low-grade malignant and high-grade malignant as follows; Pathologic variations of clinical behaviour in gastric carcinoid tumors after Capella et al 78

Benign

<1cm, confined to mucosa and submucosa, no angioinvasion.

Borderline

• Confined to mucosa and submucosa

• <1cm if angioinvasion present

• 1-2cm if no angioinvasion

Low-grade malignant

• Any functioning tumor

• Invading beyond submucosa

• 1-2cm if angioinvasion present

• >2cm, if no angioinvasion

High-grade malignant

• Atypical carcinoid or small cell carcinoma

LEIOMYOMA AND LEIOMYOSARCOMA76

Well documented gastric leiomyomas and leiomyosarcomas are extremely rare. Unlike leiomyomas, leiomyosarcomas occur in older age. Leiomyomas are composed of bland spindle cells with low or moderate cellularity and slight if any mitotic activity. The cells have eosinophilic fibrillary cytoplasm and foci of nuclear atypia. Leiomyosarcomas are tumors that show immunohistochemically evident smooth muscle differentiation. As defined in the WHO classification, leiomyomas and leiomyosarcomas are typically globally positive for desmin and smooth muscle actin, and are negative for CD34 and CD117 (KIT). Tumors with mitotic counts exceeding 10 mitoses per high power fields are classified as high-grade.

GASTROINTESTINAL STROMAL TUMORS

Gastrointestinal stromal tumors (GISTs), once classified among smooth muscle tumors are now understood to be a separate and distinct group of mesenchymal tumors specific to the gastrointestinal tract. They are the most common mesenchymal tumors of the gastrointestinal tract 79. A majority of these tumors are seen in the stomach (60-70%), but they occur anywhere in the gastrointestinal tract. These tumors may be single or multiple and vary in size from tiny intramural lesions to bulky tumor masses. They commonly present as endophytic thus producing a dumbbell appearance. They are usually well circumscribed with a gray to pink color on cut section, with areas of necrosis, hemorrhage, infarction and cystic change. The gross features, which suggest malignancy, include tumor size, and of course obvious invasion. Microscopically they have a wide range of appearances, but two basic cell types are recognized-spindle cell and epitheloid types. Mitotic rates are variable. In one study, several microscopic variants have been recognized in the spindle cell tumors (sclerosing, palisaded-vacuolated, hypercellular and sarcomatous) and the

epithelioid tumors (sclerosing, dyscohesive, hypercellular and sarcomatous)80.

GISTs of the stomach are known to exhibit KIT and PDGFRA mutations81. Immunohistochemically all GISTs show consistent positivity for CD 117 (c-kit), a tyrosine kinase receptor normally expressed by the interstitial cells of Cajal. They can also present as exophytic subserosal lesions. Some of the tumors can have both the features, this, 60% to 70% of GISTs show immunopositivity for CD34, 30% to 40% for smooth muscle actin (SMA) and around 5% for S-100 protein82. The important predictors in clinical behaviour of GISTs are the tumor size and

mitotic rate, based on which they can be grouped as follows:

Probably Benign

Maximum diameter ≤5 cm and no more than 5 mitoses per 50 HPFs.

Probably Malignant

Maximum diameter >10 cm or more than 5 mitoses per 50 HPFs.

Uncertain or Low Malignant Potential

• Gastric Tumors: Maximum diameter >5 cm and ≤ 10 cm and no more than 5 mitoses per 50 HPFs.

MALIGNANT LYMPHOMA

Gastric lymphomas constitute about 50% of all digestive tract lymphomas83. Gastric lymphoma occurs in many types, most common type being the marginal zone

lymphoma of MALT type. MALT (Mucosa Associated Lymphoid Tissue) lymphoma is an extranodal lymphoma comprising of heterogenous small B cells including marginal zone B cells (centrocyte-like) cells, monocytoid cells, small lymphocytes and scattered immunoblast and centroblast like cells. These cells infiltrate the interfollicular region and in epithelial tissues, they typically infiltrate the epithelium forming lymphoepithelial lesions. They can present either as low-grade lymphomas or intermediate/high grade lymphomas.

Low-grade lymphomas comprise about half of the cases. They present in the

distal half of the so much with giant convolutions of the mucosa mimicking hypertrophic gastritis or gastric polyps. Microscopically most of these tumors are the MALT type. They may show transmural involvement of the wall, with focal areas of plasmacytoid differentiation.

Intermediate/high-grade lymphomas present usually in the distal stomach as large lobulated (sometimes polypoid) mass, with superficial or deep ulceration.

Microscopically, they are composed of cells resembling centroblasts, but with more

abundant cytoplasm, which would sometimes give rise to a plasmablastic or immunoblastic appearance. The most important differential diagnosis is undifferentiated carcinoma, in which cases special stains to demonstrate mucin or silver impregnation methods for reticulin fibers are helpful.

The other types of lymphomas that can occur in the stomach include anaplastic

large cell lymphoma, True histiocytic lymphoma, plasmacytoma, multiple myeloma,

Peripheral T cell lymphoma and Hodgkin's lymphoma83.

SECONDARY TUMORS

Tumor metastasis to the stomach is rare. They may present as solitary or multiple lesions. Metastatic lobular carcinomas of the breast for infiltrating the gastric wall are well known. Other commonest primaries include carcinomas of the lung, pancreas, colon, breast, thyroid and prostate 76.

Helicobacter pylori

Helicobacter pylori have infected upto one half of the world's population. The infection is more common in developing countries due to poor sanitation, overcrowding and low economic status 3,4.

In 1875, German scientists documented helical shaped bacteria from stomach lining, because they were not able to culture and it was forgotten. The organism was rediscovered by Dr.Barry. J. Marshall and Dr. J.Robin Warren in the year 1983, followed by cascade of reports regarding their association with chronic gastritis, peptic ulcers of stomach, duodenum, adenocarcinoma and lymphoma3,4.

H.pylori are curvilinear, non sporulating gram negative bacilli, urease producing organism with unipolar flagellae. They measure 3.5µm in length and 0.5- 1µm in width. Recently Helicobacter heilmanii has been recognized as a second etiological agent of chronic gastric disease.

Pathogenesis of gastric mucosal injury due to H.pylori

H.pylori produces urease which converts urea to CO2 and NH 3, which in turn buffers the gastric acid and elevates the pH to 5.5 which will be suitable for the survival of the bacteria. In antral region the optimal pH is obtained easily so the anaerobic bacteria colonize in higher concentration during acute infection. The bacteria produce reductases which can convert nitrate in the food to nitrite which inturn can react with amines, amides and urease to produce carcinogenic N- nitroso compounds3,76.

Genetically the organism is hetrogenous and all strains do not cause malignancy. The organisms which are cag and VacA positive strain can cause gastric carcinoma. Thr former causes production of interleukin 8 (IL8) through nuclear factor kappa B pathway and the latter produces vacuoalating cytotoxin. Increased production of IL-8 causes inflammation which in turn leads to atrophic gastritis nd diffuse antral gastritis.

Atrophic gastritis leads to intestinal metaplasia and latter leading to intestinal adenocarcinoma. In diffuse antral gastritis lymphoid follicles and germinal centres are seen in stroma. So formation of MALT as an immune response to H.pylori infection may be an essential precursor to MALT lymphoma.

Worldwide prevalence of H. pylori ranges from 20-80%. The percentage is always on higher side in developing countries. Studies in South India and JIPMER substantiate the above point that the prevalence of H. pylori is on the higher side. Study conducted by Hamid et al in children in Puducherry showed H.pylori was seen in 61.6% of gastric lesions.

Two studies done by Dr. Ananthakrishnan et al during 1998 and 2000 concludes 77% and 67% respectively is the prevalence of H. pylori in Puducherry which is slightly higher when compared to other studies in India. The association of H.pylori and gastric carcinoma is still a controversy throughout the world. Most of the studies in India says prevalence of H. pylori is higher when compared to other parts of the world. But incidence of gastric carcinoma is comparatively less in Indian population (10.6/1,00,00) when compared to Chinese and Japanese population (32-59/1,00,000). So it is said that H. pylori could be an incidental finding and other causes like personal habits and genetic makeup could play a role in development of gastric carcinoma116,117.

Histochemical Methods and Rapid Urease Test for diagnosis of H. pylori

The diagnostic methods available for detecting H. pylori infection include serology (IgG ELISA), rapid urease test, histopathology, 13 C-urea breath test (UBT) and polymerase chain reaction (PCR) 84. There are some simple non-invasive testing methods. A urea breath test measures carbon dioxide levels after the ingestion of urea. Other more accurate methods are blood tests for serum antibodies. But, these tests do not indicate the location, extension of the infection and the type of damage to the gastric lining. People can often be infected with H. pylori and yet have no symptoms or ulcers. Invasive testing requires endoscopic examination where a biopsy is performed. Tissue samples can be used for histologic examination or a biopsy based rapid urease detection. This test requires a tissue sample which should be placed in the medium. If the organism is present, it produces a color change in the medium because of the presence of urea. Although the more advanced studies like IHC will yield a higher specificity, the cost and time is prohibitive. There are many staining procedures that are relatively quick and inexpensive6.

Rapid urease test is highly specific for H. pylori infection and a very common test used for the detection of H. pylori infection at endoscopy. As it requires a high density of bacteria, and anything that reduces the bacterial load may produce false negative tests. The diagnostic yield of rapid urease test depends on number of biopsies taken and the number of sites in the stomach that are biopsied. The sensitivity of urease test is reduced in patients who are taking proton pump inhibitors, antibiotics or bismuth compounds. This effect may reduce the sensitivity of histological examination and rapid urease testing for H. pylori on biopsies taken from recommended sites. The rapid urease test is the most frequently used test for the diagnosis of H. pylori infection in routine gastrointestinal endoscopy practice. It is extremely valuable because it gives a positive result for H. pylori infection before the patient leaves the endoscopic suite84.

Histological diagnosis of H. pylori infection is usually reserved for patients with a negative biopsy urease test or when histology was required for another reason such as exclusion of malignancy. In patients on PPI the biopsy specimen may contain low bacterial density of viable cells giving a negative urease test. This also leads to lack of H. pylori identification on histology. Of the various tests that are available for H. pylori detection, histological examination of gastric biopsy is considered the most accurate method of diagnosis. As rapid urease test can miss a low-level infection with H. pylori, a negative test should not be the sole criterion for either absence or cure of H. pylori infection. A negative diagnosis on PPI might be backed up with a serological test which should not be affected by PPI84.

Microscopic examination by H&E commonly reveals an inflammatory process of the mucosal lining. Special stains are required for the confirmation of the organism. Histologic methods range from Romanowsky, Modified Giemsa, Genta, silver stains, and IHC to fluorescent DNA probes6. H&E stain is routinely performed for the evaluation of gastric biopsies, which makes it cost effective to use. However, sensitivity of the H&E stain is low probably due to the lack of contrast between the bacteria and the surrounding tissues. The specificity of the H&E is also low due to its non-specific staining of the non-HP bacteria resident in the stomach. H&E in combination with a special stain for the bacteria may be a cost effective way of demonstrating bacteria88.

The TB stain was considered to be not so reliable stain for the detection of H.pylori organisms due to its low sensitivity and specificity. HP immunohistochemistry is an expensive and time-consuming technique with procedure length ranging from 1 hour to 24 hours. Obviously, since H.pylori organisms can be easily identified in the immunoslides, therefore sensitivity and specificity are high. Modified Giemsa is a cheap, easily applicable stain that can be performed in 15 minutes. The results are reliable and the sensitivity and specificity values are acceptable. The lack of contrast is a disadvantage of the Giemsa technique but careful observation should allow identifying the organisms. TB stain is cheap and easily applicable with an average hands on time of 4 minutes, however its sensitivity and specificity in the current study were not as good as the other stains88. WarthinStarry stain can easily identify H. pylori but it is expensive and it needs hands of experienced pathologists87. In summary, immunohistochemistry had the highest sensitivity and specificity with high interobserver agreement. However, due to its cost and the hands-on time required Giemsa stain can be considered as one of the best stain for the detection of HP due to its low cost, short hands on time required for staining and very high sensitivity and specificity combined with a high interobserver agreement88.

The acridine orange (AO) stain uses ultraviolet fluorescence in the identification of bacteria. The typical curved morphology of H pylori can easily be differentiated from other bacteria. It is quick, cheap, and reliable stain and it can be extremely useful in the identification of H pylori. The acridine orange stain may not be specific, but the morphology of H pylori is clearly visible down to the single organism.

The only disadvantage of the acridine orange stain is that the microscopic needs a fluorescent attachment and a dark room. H pylori status validated by urea breath test, biopsy urease test, and culture. Modified Giemsa stain has been confidently used by many pathologist and the results may not be reproduced by different pathologists serving different populations. But the choice of stain is a matter of personal judgement and laboratory practice. The most valuable requirement is for detection of H. pylori is diligent, enthusiastic histopathologists who can recognise the organism by whichever stain they choose85,90.