Gastric Polyps & Tumors

By : Dr. Karan Arora

• Introduction to Polyps• Classification of Polyps• Gastric Carcinoma• Endocrine Tumors• Gastric Lymphomas• Mesenchymal Tumors

GASTRIC POLYPS

Introduction

•Gastric polyps are defined as luminal lesions projecting above the plane of the mucosal surface 

•Develop as a result of epithelial/stromal cell hyperplasia, inflammation, ectopia or neoplasia

•A gastric polyp has the potential to become cancerous – most will remain benign but in a minority of cases it will progress into cancer

Classification• Enlarged Mucosal folds are also included because

there is some clinical overlap between prominent folds and polyposis

• Although histologic examination is the key to differential diagnosis, much practical diagnostic help can also be obtained by determining

▫ If a biopsy comes from a discrete polyp / from a prominent mucosal fold

▫ Whether a polyp is sessile/pedunculated▫ Whether polyps are present in other parts of GI tract▫ Whether the surrounding mucosa is normal

Peutz-Jeghers Syndrome

• Also known as Hereditory Intestinal Polyposis Syndrome

• Autosomal dominant genetic disease, characterised by development of hamartomatous polyps in GI tract and hyperpigmented macules on the lips and oral mucosa

• Caused by : Mutation of the serine/ threonine kinase gene(STK11/LKB1)

• Commonly present in childhood / adolescence

• Size : 1-3 cms.

• Surface : Coarsely lobulated with short, broad stalk

• Histologically :

▫The most useful diagnostic feature is : presence of a core of finely arborizing branches of smooth muscle from muscularis mucosae

▫The core is covered with abundant mucosa, identical with that of stomach, but often disorganized.

▫Predominantly, consist of surface and foveolar epithelium, although occasional antral glands and small cysts may be found

▫ Inflammation is usually not prominent

▫Low risk of developing into carcinoma

A 21-year-old female was referred to the department of surgery as an emergency with the complaints of abdominal pain and bilious vomiting for the past 14 daysF/H : Similar lesions in familyG/E : mucocutaneous macules noted on lipsOn Operating table, intussusception of the bowel was seen. A firm mass was palpable in the lumen of the bowel. A segmental resection was done as the mass was completely obstructing the lumen and a polypoidal mass was found. It was sent for histopathological examination.

 Fig 1(Left Upper) : Note the arborizing smooth muscle architecture unique to PJS-type polyp

 Fig : 2 (Rt Lower) : Low power microscopic view of a PJS-type polyp with pseudo-invasion

Juvenile Polyps

•Also called retention polyp

•Surface : Rounded, smooth-surfaced lesion

•Size : 1-2 cm in diameter

•Occurs due to mutation of SMAD4 gene(chromosome 18) / PTEN gene(chromosome 10)

• Histologically :

▫Consists of principally lamina propria which contains irregularly shaped cysts lined by normal gastric epithelium

▫Repeated episodes of torsion may produce stromal hemorrhage, surface ulceration, and secondary chronic inflammation

• Small, but definite risk of colorectal cancer & gastric cancer with patient with juvenile polyposis

Hyperplastic Polyps

• Also called regenerative/ hyperplaseogenous polyp

• Common in both children & adults(Most common b/w 5th & 6th decade)

• Occurs mostly at junction of pyloric & corpus mucosa

• Multiple, avg. size 1.4 cms

• Surface : coarsely lobulated

• Small polyp : Sessile, Large : short, broad stalk

•Presumed histiogenesis : Exagerrated regenerative response to mucosal damage

•Adjacent non polypoid mucosa shows chronic atrophic gastritis

•Rarely undergo malignant change(2%)

•Malignant change confined to lesions greater than 2cms

• Histologically

▫Elongated, distorted & branched gastric foveolae

▫Often abundant lamina propria, which may be inflammed & edematous

▫Frequently foveolar cells are hypertrophic with excess superficial cytoplasm with/without intestinal metaplasia

▫Nuclei are typically bland(resemble normal gastric pit) but in areas of heavy inflammation , regeneration can produce nuclear enlargement with prominent nucleoli

Irregular Epithelial proliferation, cyst formation, and excess of lamina propria

Fig A : Hyperplastic Polyp showing cork screw shaped foveolar glandFig B : Polyp with Ulceration

Fundic Gland Polyp

• Accounts for 50% of all gastric polyps

• Occur as isolated sporadic lesion that are usually of little clinical significance

• However, fundic gland polyposis(10 or more polyps) has been described in two clinical situations

▫Following drug therapy for gastric acid suppression

▫ In Familial adenomatous polyposis(FAP) where many hundred’s of polyp are present

•In FAP

▫The polyps are true neoplastic lesions, showing mutation in APC gene

▫25-50% prevalence of dysplasia in the foveolar epithelium

▫May rarely give rise to adenocarcinoma

•In sporadic & drug therapy related polyps

▫They are non dysplastic

▫Do not show APC mutation

▫May have point mutation of beta-catenin (CTNNB1) gene

•Macroscopically : Minute mucosal bumps : 1-16mm in diameter, occur in gastric body & fundus

•Microscopically :

▫Single/ small groups of cystically dilated fundic glands, lined by attenuated but otherwise normal layer of chief cells, parietal cells & mucous neck cells

▫Inflammation is typically minimal/ absent

Consists of dilated gland lined by an attenuated , but otherwise normal epithelium

Adenomas

• Comprise 7-10 % of all gastric polyps

• Most are sessile & grow in tubulo villous / pure villous pattern

• Pure pedunculated tubular lesions are rare

• Usually Solitary lesions < 2cms

• Histologically : Two types of lesion

▫ Adenomas showing intestinal differentiation(goblet cells &/or paneth cells)

▫ Adenomas showing gastric differentiation(columnar cells containing neutral mucin)

• Polyps larger than 2cms & those with intestinal differentiation have significant chance of becoming malignant(Overall, carcinoma may be present upto 30% of gastric adenomas)

• Adenomas

▫With intestinal differentiation , arise in background mucosa that shows intestinal metaplasia

▫With gastric differentiation , arise in mucosa that is either normal/shows minor inflammatory feature

• By definition, all GI adenomas have epithelial dysplasia that is classified as low/high grade

• Both grades include :

▫ Enlargement, elongation & hyperchromasia of epithelial cell nuclei

▫ Epithelial crowding

▫ Pseudostratification

• High grade dysplasia includes more cytologic atypia with irregular artitecture, including glandular budding & gland within gland or cribriform structures

Villous adenoma of stomach

Zollinger -Ellison Syndrome•Triad of

▫Gastric acid hypersecretion▫Severe peptic ulceration▫Non beta cell islet tumor of

pancreas(gastrinoma)

• Increase in mass of body glands with normal sized antral glands & gastric foveolae(d/t excess production of gastrin)

•Excess gastrin has trophic effect on parietal cells, causing them to enlarge & proliferate

• Gross :

▫Mucosal folds in gastric body are enlarged & thrown into cerebriform pattern

• Histologically

▫Gland thickness is expanded approx 2 times of normal

▫Glands consist of hypertrophied & hyperplastic parietal cells that appear to crowd out chief & mucous neck cells

▫Gland lumen may be dilated , producing small cysts

▫Hyperplastic endocrine cells may also be present in the corpus glands

Menetrier Disease

• Poorly defined entity

• Diagnosis criteria for this disease (Given by Appleman) includes

▫Giant Mucosal folds involving the corpus & possibly antrum

▫Low acid production, even after stimulation

▫Mucosal protein loss

▫Histologic findings of corpus foveolar hyperplasia & glandular atrophy

•Histologic features :

▫Elongation of gastric foveolae on the surface of folds & may have cork screw appearance

▫Often cystically dilated with mucus accumulation

▫Cysts extends into deeper mucosal layer & even occasionally the submucosa, with resulting corpus gland atrophy

Menetriers disease showing foveolar hyperplasia & cyst formation

GASTRIC TUMORS

GASTRIC CARCINOMA

• Majority of gastric cancers are adenocarcinoma

• Definition of W.H.O▫“A malignant epithelial tumor of stomach mucosa

with glandular differentiation”

• Early symptoms resemble those of chronic gastritis, including dyspepsia, dysphagia & nausea

• As a result these tumors are often discovered at advanced stages, when symptoms such as weight loss, anorexia etc. trigger further diagnostic evaluation

Epidemiology

• Geographical Distribution

▫ In Japan & eastern europe, the incidence is upto 20 fold higher than in north america & south east asia

• Time Trends

▫ Decline in incidence has been observed worldwide from past few decades

▫ Reason : Decrease consumption of dietary carcinogen such as : N-Nitroso compounds & benzo(a) pyrene

• Age & Sex Distribution

▫ Rare in age < 30 yrs., highest in old age groups

▫ Intestinal type : Male> Female

▫ Diffuse type : Affects young females more(d/t hereditary characterstics : germline mutation of CDH1 gene)

Aetiology

• Diet

▫ Increased Risk Smoked or cured meats or fish, pickeled vegetables, chilli

peppers Exposure to nitrosamines, alcohol, tobacco & Inorganic

dusts

▫Decreased Risk Fruits, vegetables, carotenoids, folates etc.

• Bile Reflux

▫ Increased Risk after 5-10 yrs. Of gastric surgery (Bilroth II) which increases Bile reflux

•Helicobacter Pylori Infection

▫Strong association with the organism

▫Induces the phenotypic change & leads to formation of adenocarcinoma

▫Sequential Steps involved

Chronic gastritis Multifocal atrophy Intestinal metaplasia Intraepithelial neoplasia

•Precursor lesion

▫Gastritis & Intestinal metaplasia▫Intraepithelial neoplasia(dysplasia)

•Location

▫Most frequent site of sub cardial stomach cancer is the distal stomach i.e the antro-pyloric region, more on lesser curvature than greater curvature

• Classification

• Two widely used : Lauren & WHO

▫ Lauren

List three histologic types

Intestinal▫ These form recognizable glands that range from well differentiated to

moderately differentiated tumors, sometimes with poorly differentiated with advancing margin.

▫ Typically arise on background of intestinal metaplasia

Diffuse▫ Consist of poorly cohesive cells diffusely infilterating the gastric wall

with little / no gland formation.▫ The cells appear round & small arranged as single/clustered in abortive,

lacy gland like/reticular formation. These tumor resemble signet ring type as classified in WHO classification

▫ Most cases of LEATHER BOTTLE STOMACH(linitis plastica) is classified as diffuse

▫ Mitotic rate is lower in diffuse than intestinal type▫ Desmoplasia is more pronounced▫ Inflammation is less evident

Mixed

Leather bottle stomach

Adenocarcinoma of stomach & intestinal metaplasia

Intestinal type adenocarcinoma of stomach. Well formed glands with lack of cytoplasmic mucin

Diffuse carcinoma of stomach. Shows submucosal infiltration by single cells & small strings of cell

Diffuse carcinoma , showing multiple signet ring cells

•W.H.O classification

▫Tubular

Consist of prominent dilated/slit like & branching tubules varying in their diameter; acinar structures may be present

Tumor cells are columnar, cuboidal or flattened by intraluminal mucin

Clear cells may also be present Cytologic atypia varies from low to high grade Poorly differentiated variant is sometimes called

solid carcinoma Tumors with prominent lymphoid stroma are

sometimes called medullary carcinoma/ carcinomas with lymphoid stroma

▫Papillary

Well differentiated exophytic carcinomas with finger like processes lined by cylindrical/ cuboidal cells supported by fibro vascular connective tissue cores

Cells maintain their polarity Invading tumor edge is usually sharply

demarcated from surrounding structures from surrounding structures

May be infilterated by acute & chronic inflammatory cells

▫Mucinous

By definition >50% tumors consists of extracellular mucinous pools

Two major growth pattern Glands lined by a columnar mucous secreting

epithelium together with interstitial mucin Chains or irregular cell clusters floating freely

in mucinous flakes

Signet ring cells when present do not dominate the picture

▫Signet ring cell carcinoma

>50 % of tumor consist of isolated/small groups of malignant cells containing intracytoplasmic mucin

Tumor cells have 5 morphologies

1. Nuclei push against cell membranes creating a classical signet ring cell appearance d/t an expanded, globoid, optically clear cytoplasm. These contain acid mucin & stain with Alcian blue at pH 2.5

2. Other diffuse carcinomas contain cells with central nuclei resembling histiocytes & show little/no mitotis

3. Small, deeply eosinophilic cells with prominent but minute, cytoplasmic granules containing neutral mucin

4. Small cells with little/ no mucin

5. Anaplastic cells with little/ no mucin

▫Signet ring cell carcinoma(contd.)

Special stains :

Mucin detection : PAS, mucicarmine, Alcian blue

IHC : Cytokeratin

Several Condition which mimic Signet Ring carcinoma :

Signet ring lymphoma Lamina propria muciphages Xanthomas Detached/dying cells associated with gastritis

Rare variants of carcinoma

•Adenosquamous•Undifferentiated carcinoma•Mixed adenocarcinoma-carcinoid•Small cell carcinoma•Parietal cell carcinoma•Endodermal sinus tumor•Hepatoid carcinoma

Early gastric cancer

• Carcinoma limited to mucosa / mucosa & submucosa regardless of nodal status

• Lesions may be categorised as : ▫Flat▫Elevated▫Depressed▫Excavated▫Combined forms

• Most tumors are 2cms or less in diameter

• Importance of correctly identifying early gastric cancer lies in excellent result of surgical treatment

Grading• Well differentiated

▫ An adenocarcinoma with well formed glands, often resembling metastatic intestinal epithelium

▫ >95% consist of glands

• Moderately differentiated

▫ Intermediate between well & poorly differentiated

▫ 50-95% consist of glands

• Poorly differentiated

▫ Adenocarcinomas consisting of irregular glands recognised with difficulty/single cells that remain isolated or/are arranged in small/large clusters with mucin secretion or acinar structures

▫ 49% or < consist of glands

Endocrine tumors

• Definition of W.H.O

▫“Most endocrine tumors of stomach are well differentiated, non functioning enterochromaffin-like(ECL) cell carcinoids arising from the oxyntic mucosa in the corpus /fundus”

• Three types

▫Type I : associated with autoimmune chronic atrophic gastritis

▫Type II : associated with MEN-I & Z.E syndrome

▫Type III : sporadic

• Type I

▫ Most common(74%)

▫ Average age of onset is 63 yrs.

▫ Sex : F>M(2.5 :1)

▫ Underlying cause : CAG from pernicious anemia

▫ Associated with achlorhydria, antral G cell hyperplasia & hypergastremia

▫ Pathogenesis :

Gastrin is trophic for ECL, which proliferate resulting in initially in simple hyperplasia and later into nodular hyperplasia & finally into neoplasia

•Type I(contd.)

▫Histologically :

Carcinoid tumor appear as small cluster/ribbons of cells at base of mucosa

Individual cells are regular, with rounded nuclei having diffuse chromatin pattern

Cytoplasm is grayish & not obviously granular

Immunopositive : Chromogranin , synaptophysin

• Type II

▫Constitute 6 % of all gastric endocrine tumors

▫Mean Age : 50 yrs.

▫Sex : M=F

▫Morphology :

Almost same as type I, occasionally may become large & metastasize to regional nodes

Background mucosa shows parietal cell hyperplasia

• Type III

▫Constitute 13% of all gastric endocrine tumors

▫Mean Age : 55 yrs.

▫Sex : M>F(2.8:1)

▫Not accompanied by hypergastrinemia/atrophic gastritis/pernicious anemia

▫Commonly found in corpus

▫Behave in malignant fashion if lesion is > 2cms/show angio invasion/deep muscle invasion

GI carcinoid tumor (neuroendocrine carcinoma). A, Gross cross-section of a submucosal tumor nodule. B, Microscopically the nodule is composed of tumor cells embedded in dense fibrous tissue. C, In other areas, the tumor has spread extensively within mucosal lymphatic channels. D, High magnification shows the bland cytology of carcinoid tumors. The chromatin texture, with fine and coarse clumps, is frequently described as a "salt and pepper" pattern. Despite their innocuous appearance, carcinoids can be extremely aggressive clinically. E, Electron microscopy reveals cytoplasmic dense core neurosecretory granules

Extreme endocrine cell hyperplasia is present, resulting in microcarcinoid nodules in gastric mucosa

GASTRIC LYMPHOMAS

• Definition of WHO

▫ “Primary gastric lymphomas are defined as lymphomas originating from the stomach & contiguous lymph nodes”

• Lymphomas at this site is considered as primary if the main bulk of disease is located in stomach

• Majority of gastric lymphomas are high grade B-cell lymphomas, some of which have developed through progression from low grade lyphomas of mucosa associated lymphoid tissue(MALT)

• The low grade lesions are exclusively B-cell MALT lyphomas

• 40% NHL arise in extranodal site, out of which GI tract is the most commonest

• Constitutes over 10 % of all gastric malignancy

• Age : Common in >50 yrs

• Sex : M=F

• Etiology

▫H. Pylori▫Immunosuppression

MALT Lymphomas• Pathogenesis

▫The normal gastric mucosa contains scattered lymphocytes & plasma cells but is devoid of organised lymphoid tissue

▫First step in development of primary gastric lymphoma is acquisition of organised lymphoid tissue from which lymphoma can arise

▫ In most cases it is associated with H.Pylori

▫H. Pylori do not directly stimulate MALT lymphoma cells but cause secretion of IL-2 from adjacent T cells & induce IL-2 receptors on tumor cells themselves

• MALT lymphoma is low grade lymphoma

• It may transform to high grade i.e DLBCL

• Five cardinal histologic features of MALT lymphoma

▫An infilterate of small lymphocyte & small cleaved follicle centre(Centrocyte-like - CCL) cells

▫Lymphoid follicles

▫Neoplastic plasma cells

▫Lymphoepithelial lesions

▫Dutcher bodies(PAS-positive intranuclear inclusion)

▫Lymphocytic infiltrating the epithelium of the stomach is highly characteristic of MALT lymphomas, but can also be present in lymphocytic gastritis

▫To be suggestive of lymphoma, the infiltrate must be present as a lymphoepithelial lesion(a discrete cluster of three/more lymphocyte)

▫In lymphocytic gastritis , the lymphocytes(Which are T cells rather than B cells) are usually present as single cells within the epithelium

▫Immunophenotype

Positive : CD20 Negative : CD5,CD10, Bcl-6, Cyclin D1

Note : CD5 negativity is useful in differentiating from other small cell lymphoma

MALT lymphoma producing expansion of submucosa in an ill defined nodular pattern & showing follicular colonization

Predominantly intermediate sized cells(cleaved cells) with less larger cells

Lymphoepithelial lesion from MALT lymphoma

Diffuse Large Cell B-cell Lymphomas

▫Most high grade gastric lymphomas are DLBCL

▫Major diagnostic challenge is to separate DLBCL from poorly differentiated carcinoma

▫Lymphoma cells tend to infiltrate widely in the lamina propria in a sheet like fashion, but they often spare existing gastric pits & glands

▫In contrast to MALT lymphomas, lymphoepitheial lesion is not a common finding

DLBCL(Contd.)

▫Carcinomas tend to destroy mucosal structures as they infiltrate

▫Cells of lymphoma are totally non cohesive with no tendency to form clumps/cords

▫Nuclei of DLBCL are characteristically

vesicular with prominent nucleoli & nuclear membrane

DLBCL of stomach

Other B-Cell lymphomas

▫Mantle Cell Lymphoma

▫Follicular Lymphoma

▫Burkitt Lymphoma

MESENCHYMAL TUMORS• Definition of WHO

▫“Most gastrointestinal mesenchymal neoplasms are GIST/smooth muscle types”

• Previously the term GIST was applied to mesenchymal tumors of all type

• At, present the diagnosis should be restricted to neoplasm arising from Interstitial cells of Cajal(GI pacemaker cells)

• Tumors arising from smooth muscle should be called leiomyoma/leiomyosarcoma & thise arising from the nerves should be called shwannoma/neurosarcoma

GIST(Gastrointestinal Stromal Tumor)

•Accounts for 2% of all malignant gastric tumors

•Typically defined as “tumors whose behaviour is driven by mutations in Kit gene/PDGFRA gene and may/may not stain positive for kit”

•Age : B/w 5th & 8th decade

•Sex : M=F

GIST(Contd.)• Pathophysiology

▫ Thought to arise from interstitial cells of cajal(ICC)

▫ What is ICC ?

The Interstitial cell of Cajal (ICC) is a type of  interstitial cell found in the gastrointestinal tract that serves as a pacemaker which creates the basal electrical rythym leading to contraction of the smooth muscle(peristalsis)

▫ Most of GIST arise because of mutation of c-kit gene

▫ C-kit/CD117 is expressed in ICC

▫ Most are sporadic, some are hereditary

GIST(Contd.)• Gross

▫Solitary rounded or lobulated lesions with a clearly defined margin

▫Primarily involve the muscularis propria & submucosa

▫Larger tumor bulge into gastric lumen & have attenuated mucosa covering their surface

• C/S

▫Flat, whorled appearance with tumor substance usually firm with foci of necrosis/hemorrhage

▫Large tumors may be cystic in middle

GIST(Contd.)

•Eight different histologic subtypes

▫Spindle(4) & Epithelioid(4)

▫Spindle type

20% of all stromal tumor

Subtypes :

Sclerosing(most common) Palisading vacuolated Hypercellular Sarcomatous

GIST(Contd.)▫Spindle type(contd.)

Sclerosing

▫Composed of interlacing fascicles & whorls of uniform elongated cells, with cigar-shaped vesicular nuclei & eosinophilic cytoplasm

Palisading

▫Close resemblance to schwannoma

Hypercellular

▫Tightly packed uniform spindle cell without significant atypia/mitotic activity

Sarcomatous

▫Significant mitotic activity & pleomorphism

GIST(Contd.)▫ Epithelioid type

Involve the corpus & antrum

Subtypes

Sclerosing

▫ Syncytial pattern, composed of round cells with clear/lightly eosinophilic cytoplasm

▫ Clearing of cytoplasm is result of fixation artefact▫ Sometimes vacuolation in cytoplasm is eccentric giving false

impression of signet ring cells

Dyscohesive variant

▫ Epithelioid cells surrounded by lacunar spaces

Hypercellular

Sarcomatous

• Immunophenotype : 95% positive for CD117

• Prognosis▫ Four broad group depending upon gross size & mitotic

activity/50 hpf

Very Low malignant potential Less than 2cms with <5 mitoses/50 hpf

Low malignant potential 2-5cms with <5 mitoses/50 hpf

Intermediate malignant potential <5cms with 6-10 mitoses/50 hpf

▫ Or 5-10cms with <5 mitoses/50 hpf

High malignant potential >5cms with >5 mitoses/50 hpf

▫ Or >10cms with any number of mitoses

▫ Or Any size with >10 mitoses/ hpf

Low grade spindle cell GIST composed of interlacing fascicles of cells with cigar shaped nuclei

Epitheloid GIST with rounded nuclei & clear cytoplasm

Malignant Epitheloid GIST. Note : cellularity, pleomorphism & mitoses

References

•Robbins : 8th Edition•Sternberg : 5th Edition•WHO classification of tumors•Internet