patoloji-ders-notlari

Title

Serdar Balcı

Tumors of Upper GI Tract

Serdar BALCI, MD

TUMORS OF ORAL CAVITY

Squamous Cell Carcinoma

• Field cancerization
  • Multiple primary tumors develop independently
  • Years of chronic mucosal exposure to carcinogens
• Two distinct pathogenic pathways
  • Chronic alcohol and tobacco (both smoked and chewed) users
    • TP53, p63 and NOTCH1
  • HPV related
    • Tonsillar crypts, base of the tongue
    • HPV-16
    • fewer mutations
    • overexpress p16, a cyclin-dependent kinase inhibitor

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

TUMORS OF SALIVARY GLANDS

Robbins and Cotran Pathologic Basis of Disease

65% to 80% arise within the parotid

10% in the submandibular gland

remainder in the minor salivary glands, including the sublingual glands

15% to 30% of tumors in the parotid glands are malignant

40% of submandibular, 50% of minor salivary gland, and 70% to 90% of sublingual tumors are cancerous

Likelihood that a salivary gland tumor is malignant is inversely proportional, roughly, to the size of the gland

Pleomorphic adenoma

overexpress the transcription factor PLAG1

Robbins and Cotran Pathologic Basis of Disease

Pleomorphic adenoma

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

Mucoepidermoid carcinoma

chromosome rearrangements involving MAML2

**signaling protein in the Notch pathway **

Robbins and Cotran Pathologic Basis of Disease

**Adenoid cystic carcinoma **

Robbins and Cotran Pathologic Basis of Disease

**Adenoid cystic carcinoma **

Robbins and Cotran Pathologic Basis of Disease

ODONTOGENIC CYSTS AND TUMORS

Odontogenic Cysts and Tumors

Jaws are a common site of epithelium-lined cysts derived from odontogenic remnants

Odontogenic keratocyst is locally aggressive, with a high recurrence rate

Periapical cyst is a reactive, inflammatory lesion associated with caries or dental trauma

The most common odontogenic tumors are ameloblastoma and odontoma

ESOPHAGIAL TUMORS

ESOPHAGEAL ADENOCARCINOMA

Esophageal adenocarcinoma

Arises in a background of Barrett esophagus and long-standing GERD

Risk is greater with dysplasia, further increased by tobacco use, obesity, and previous radiation therapy

Reduced adenocarcinoma risk is associated with diets rich in fresh fruits and vegetables

• Whites
• 7x more common in male
• Highest in developed Western countries
  • US, UK, Canada, Australia, Netherlands
• Lowest in Korea, Thailand, Japan, and Ecuador
• The incidence has increased markedly since 1970, more rapidly than for almost any other cancer
  • From 5% to half of all esophageal cancers in the United States

N Engl J Med 2014;371:2499-509

Progression of Barrett esophagus to adenocarcinoma

Stepwise acquisition of genetic and epigenetic changes

TP53 mutation are often present at early stages of esophageal adenocarcinoma

• Usually occurs in the distal third
• May invade the adjacent gastric cardia
• Early lesions
  • flat or raised patches in otherwise intact mucosa
• Later
  • large exophytic masses, infiltrate diffusely, or ulcerate and invade deeply

Robbins Basic Pathology

Esophageal adenocarcinoma

Barrett esophagus frequently is present adjacent to the tumor

Tumors typically produce mucin and form glands

Robbins Basic Pathology

ESOPHAGIAL SQUAMOUS CELL CARCINOMA

Squamous Cell Carcinoma

>45 years of age

4x more common in males

alcohol and tobacco use, poverty, caustic esophageal injury, achalasia, Plummer-Vinson syndrome, frequent consumption of very hot beverages, and previous radiation therapy to the mediastinum

6x more common in African Americans than in whites

Highest incidences are Iran, East Anatolia, central China, Hong Kong, Argentina, Brazil, and South Africa

Use of alcohol and tobacco

Nutritional deficiencies

Polycyclic hydrocarbons, nitrosamines, fungus-contaminated foods

HPV infection in high-risk but not in low-risk regions

**Half of squamous cell carcinomas occur in the middle third of the esophagus **

Begins as an in situ lesion in the form of squamous dysplasia

Early lesions appear as small, gray-white plaquelike thickenings

Polypoid and protrude into and obstruct the lumen

most frequently in the midesophagus

commonly causes strictures

Robbins Basic Pathology

Squamous Cell Carcinoma

• Most squamous cell carcinomas are moderately to well differentiated
• Other morphologic types
  • Verrucous squamous cell carcinoma
  • Spindle cell carcinoma
  • Basaloid squamous cell carcinoma

Robbins Basic Pathology

Spread

rich submucosal lymphatic network

circumferential and longitudinal spread

intramural tumor nodules

Upper third favor cervical lymph nodes

Middle third favor mediastinal, paratracheal, and tracheobronchial nodes

Lower third spread to gastric and celiac nodes

N Engl J Med 2014;371:2499-509

NEOPLASTIC DISEASES OF THE STOMACH

GASTRIC POLYPS

Gastric Polyps

5% of upper gastrointestinal tract endoscopies

Epithelial or stromal cell hyperplasia, inflammation, ectopia, or neoplasia

Inflammatory and Hyperplastic Polyps

• 75% of all gastric polyps
• 50 and 60 years of age
• background of chronic gastritis
  • initiates the injury and reactive hyperplasia that cause polyp growth
  • If associated with H. pylori gastritis, regress after bacterial eradication

Multiple

Characteristically ovoid in shape

<1 cm in diameter

covered by a smooth surface

Irregular, cystically dilated, and elongated foveolar glands

Lamina propria edematous with variable degrees of acute and chronic inflammation

Dysplasia increases in risk >1.5 cm

Inflammatory and Hyperplastic Polyps

Robbins and Cotran Pathologic Basis of Disease

Fundic Gland Polyps

• Sporadically
• Familial adenomatous polyposis (FAP)
• No neoplastic potential
• Incidence has increased markedly
  • use of proton pump inhibitors
• Reduced acid → increased gastrin → glandular hyperplasia
• Asymptomatic or nausea, vomiting, or epigastric pain
• Well-circumscribed polyps
• Gastric body and fundus
• Multiple, and are composed of cystically dilated, irregular glands lined by flattened parietal and chief cells

FLETCHER Diagnostic Histopathology of Tumors 4 th __ Ed__

Gastric Adenoma

10% of all gastric polyps

50-60 years of age

Males are affected 3x more

Adenocarcinoma risk increase >2cm

Carcinoma may be present in up to 30% of gastric adenomas

Robbins and Cotran Pathologic Basis of Disease

• Most commonly in antrum
• Intestinal-type columnar epithelium
• By definition, all gastrointestinal adenomas exhibit epithelial dysplasia
  • low- or high-grade

Robbins and Cotran Pathologic Basis of Disease

GASTRIC ADENOCARCINOMA

Gastric Adenocarcinoma

• Most common malignancy of the stomach
• >90% of all gastric cancers
• 20x higher in Japan, Chile, Costa Rica, and Eastern Europe than in North America, northern Europe, Africa, and Southeast Asia
• In Japan, 35% of newly detected cases are early gastric cancer, or tumors limited to the mucosa and submucosa
• Decrease in overall gastric adenocarcinoma incidence
  • cancer of the gastric cardia is on the rise
  • related to Barrett?, chronic GERD? and obesity?

Pathogenesis of Gastric cancers

Genetically heterogeneous

Mutations

H.pylori

EBV

Mutations in Gastric Cancer

• Majority not hereditary
• Familial gastric cancers
  • Diffuse
  • intestinal

Familial Gastric Cancer

• Diffuse type
• Germline mutations in CDH1
  • encodes E-cadherin
• CDH1 mutations
  • present 50% of diffuse gastric tumors
• E-cadherin
  • expression decreased in the rest
  • often by methylation of the CDH1 promoter

Familial adenomatous polyposis

Germline mutations in adenomatous polyposis coli ( APC) genes

Increased risk of intestinal-type gastric cancer

Sporadic gastric cancer

• Sporadic intestinal-type gastric cancer
  • acquired mutations of β-catenin
    • binds to both E-cadherin and APC protein
  • microsatellite instability
  • hypermethylation of genes
    • TGFβRII, BAX, IGFRII, p16/INK4a
• Sporadic gastric cancers of both histologic types
  • TP53 mutations

H. pylori

• Increased production of proinflammatory proteins
  • interleukin-1β (IL-1β)
  • tumor necrosis factor (TNF)
• Polymorphisms associated with enhanced production of cytokines
• Increased risk of chronic gastritis-associated intestinal-type gastric cancer with co-existing H. pylori infection

Epstein-Barr virus

• 10% of gastric adenocarcinomas are associated with EBV
• EBV episomes in these tumors frequently are clonal
  • infection preceded neoplastic transformation
• TP53 mutations are uncommon in EBV-positive gastric tumors
  • distinct molecular pathogenesis
• proximal stomach
• diffuse morphology with a marked lymphocytic infiltrate

Her2 amplification

• Current important targeted therapy
• ToGA trial
• Immunohistochemistry
  • cerbB2
• In situ hybridisation
  • CISH
  • FISH

Lauren classification

intestinal type

diffuse type

bulky

broad cohesive fronts

exophytic mass or an ulcerated tumor

glandular structures similar to esophageal and colonic adenocarcinoma

apical mucin vacuoles, and abundant mucin may be present in gland lumina

• Signet ring cells
  • large cytoplasmic mucin vacuoles
  • peripherally displaced, crescent-shaped nuclei
• infiltrative growth
• Cells infiltrate mucosa and stomach wall individually or in small clusters
• desmoplastic reaction
• leather bottle (Matara mide)
• linitis plastica

**Intestinal-type adenocarcinoma **

Robbins Basic Pathology

**Intestinal-type adenocarcinoma **

**Diffuse-type adenocarcinoma **

Robbins Basic Pathology

**Diffuse-type adenocarcinoma **

Robbins Basic Pathology

Gastric Cancer

Intestinal-type

diffuse gastric cancer

• more in high-risk areas
• precursor lesions
  • flat dysplasia and adenomas
• mean age at presentation 55 years
• male-to-female ratio is 2 : 1
• Decrease in incidence
  • maybe due to decrease in atrophic gastritis and intestinal metaplasia

incidence is relatively uniform across countries

no identified precursor lesions

occurs at similar frequencies in males and females

The Cancer Genome Atlas (TCGA) projectMolecular classification

Chromosomal instability

Tumours positive for Epstein–Barr virus

genomically stable tumours

microsatellite unstable tumours

Nature 2014

doi:10.1038/nature13480

Nature 2014

doi:10.1038/nature13480

Gastric Cancer

• TNM is important as a prognostic factor
  • The depth of invasion
  • Extent of nodal metastasis
  • Distant metastasis at the time of diagnosis
• Local invasion into the duodenum, pancreas, and retroperitoneum is characteristic
• Surgical resection is the treatment choice
• 5-year survival rate for early gastric cancer can exceed 90%, even if lymph node metastases are present
• 5-year survival rate for advanced gastric cancer remains below 20%

Early Gastric Cancer

Tumors limited to mucosa

Can be resected by endoscopic mucosal resection

Common in Japan

GASTRIC LYMPHOMA

Gastric Lymphoma

• 5% of all gastric malignancies are primary lymphomas
• MALTomas
  • most common
  • indolent extranodal marginal zone B cell lymphoma
  • lymphomas of mucosa-associated lymphoid tissue (MALT)
  • H.pylori
• Diffuse large B cell lymphoma

Gastric Lymphoma

Lymphoepithelial lesions

Robbins and Cotran Pathologic Basis of Disease

Neuroendocrine Tumors

• Carcinoid Tumor
• May be associated with
  • endocrine cell hyperplasia
  • Chronic atrophic gastritis
  • Zollinger-Ellison syndrome
• Grade
  • based on mitotic activity
  • fraction of cells immunohistochemcially positive for Ki67, a mitotic marker
• Localization, extent and presence of atrophy and intestinal metaplasia are important prognostically
• High-grade neuroendocrine tumors
  • neuroendocrine carcinoma

intramural or submucosal masses

small polypoid lesions

yellow or tan in appearance

form intense desmoplastic reaction that may cause kinking of the bowel and obstruction

Robbins Basic Pathology

Neuroendocrine Tumor

islands, trabeculae, strands, glands, or sheets of uniform cells

scant, pink granular cytoplasm

round to oval stippled nucleus

salt and pepper chromatin

Robbins Basic Pathology

Location of neuroendocrine tumors

• Foregut
  • stomach, duodenum proximal to the ligament of Treitz, and esophagus
  • rarely metastasize
  • cured by resection
  • Duodenal gastrin-producing carcinoid tumors, gastrinomas, have been associated with proton pump inhibitor therapy
• Midgut
  • jejunum and ileum
  • often multiple
  • tend to be aggressive
  • greater depth of local invasion, increased size, and presence of necrosis and mitosis are associated with poor outcome
• Hindgut
  • appendix and colorectum
  • discovered incidentally
  • appendix NETs occur at any age and are almost uniformly benign
  • Rectal carcinoid tumors tend to produce polypeptide hormones and may manifest with abdominal pain and weight loss; they only occasionally metastasize

MESENCHYMAL NEOPLASMS

Mesenchymal neoplasms

Leiomyoma, leiomyosarcoma

Schwannomas

Glomus tumors

Gastrointestinal Stromal Tumor

Gastrointestinal Stromal Tumor

• slightly more common in males
• 60 years of age
• <10% occurr in persons <40 years of age
• **interstitial cells of Cajal **
  • express c-KIT
  • located in the muscularis propria
  • pacemaker cells for gut peristalsis
• c-KIT mutations
  • 75-80%
  • gain-of-function mutation
  • **tyrosine kinase **
  • receptor for stem cell factor
• PDGFRA
  • 8%
  • mutations activate a related tyrosine kinase, platelet-derived growth factor receptor A
• either mutation is sufficient, almost never found together

GIST

• Solitary
• Well-circumscribed
• Fleshy
• submucosal mass
• Size (5cm, 10cm cut-offs), mitotic count are important
• Targeted therapy
  • imatinib

Robbins and Cotran Pathologic Basis of Disease

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas