patoloji-ders-notlari

Alt GIS Tümörleri

Serdar Balcı

Alt GIS tümörleri

Dr. Serdar BALCI

https://sites.google.com/view/drserdarbalci/ https://www.serdarbalci.com/

Polipler

• En sık kolonda
• Özefagus, mide, ince barsakta da olabilir
• Sapsız olanlara sesil polip denir
• En sık görülen neoplastik polip adenom
• Non-neoplastik kolon polipleri
  • Inflamatuar, hamartomatöz, hiperplastik

Polyps

İnflamatuar polipler

• Kronik hasar ve tamir sonucu inflame, rekatif mukozadan oluşurlar
• Soliter rektal ülse sendromu sonrası oluşan polip
  • Rektal kanama, mukus akıntısı, anterior duvarda inflamasyon
  • Anorektal sfinkterde relaksasyon sorunu

Robbins and Cotran Pathologic Basis of Disease

Hamartomatöz polipler

Sporadik

Genetik, akkiz sendromlarla ilişkili

Robbins Basic Pathology

Juvenil Polipler

• En sık görülen hamartomatöz polip
• <5 yaş
• Rektum
• Rektal kanama, prolaps
• Sporadik olanlar soliter
• Autosomal dominant juvenil polypo zis sendromu 3-100 polip
  • Kolektomi
• Displazi küçük ibr kısmında olur (sendrom ilişkili)
  • Sendrom adenokarsinom gelişimi açısından riskli
• Mukozadaki hiperplazi, transforming growth factor-β (TGF-β) yolağı ile ilişkili

SAplı, düzgün yüzeyli, kırmızı lezyonlar

<3 cm

Kesit yüzünde kistik

Müsin ve inflamasyon kalıntısından oluşan debri

Robbins Basic Pathology

Peutz-Jeghers Sendromu

• Nadir otozomal dominant
• Multiple GIS polipleri ve mukokütenöz pigmentasyon
• Malignite riskinde artış: kolon, pankreas, meme, akciğer, over, uterus, testis
• LKB1/STK11 fonksiyon kaybına neden olan mutasyon, germline heterozigot ve sporadik vakalarda var
• Polipler çoğunlukla ince barsakta
  • mide, kolon, mesane, akciğerde de olabiliyor

İri ve saplı

Lobüle kontur

Dallanan yumuşak doku, düz kas, lamina propria ve bezler

Epitel normal

Peutz-Jeghers polyp

Kompleks yapı ve düz kas demetleri ile ayrılır

Robbins Basic Pathology

Hiperplastik polipler

Sık görülen epitelyal proliferasyonlar

6-7 dekad

Epitel hücre döngüsünde azalma, yüzeyden epitel dökülmesinde azalma, goblet hücrelerinde birikme

Malign potansiyeli yok, sesil serrated adenomlardan ayrılmalı

Sol kolon

<5mm

Düzgün sınırlı, nodüler mukoza kabarıklığı

Multipl, sigmoid ve rektum

Robbins Basic Pathology

İrregüler birikim gösteren epitel hücreleri

Robbins Basic Pathology

Robbins Basic Pathology

Tufting results from epithelial overcrowding

Epitel kalabalıklaşması testere benzeri serrated görünüm verir

Robbins Basic Pathology

Adenom

GIS neoplastik kitle lezyonu

Mukozal çıkıntı, polip oluştururlar

Robbins Basic Pathology

Adenomlar

Epitel displazisi

Küçük, saplı ya da büyük sesil

Cinsiyetler arası fark yok

Batı dünyasında 50 yaş üstü yetişkinlerin %50’sinde

Kolorektal kanser öncülleri

Takip kolonoskopi

fibromuscular stalk

Robbins and Cotran Pathologic Basis of Disease

Tübüler adenom, düzgün yüzey, yuvarlak glandüler yapılar

Robbins Basic Pathology

Villöz adenom

Uzun, ince çıkıntılar, ince barsak villuslarına benzer

Robbins Basic Pathology

Nükleer hiperkromazi, elongasyon, sıralanma artışı

Değişiklikler yüzeyde daha belirgi, kriptten ayrıldıkça diferasnsiayasyon kaybı oluyor

Robbins Basic Pathology

Sessile serrated adenoma:

Goblet hücreleri ile döşeli

Belirign displazi yok

Hiperplastik polipten değişikliklerin derine kadar (kripte kadar) inmesi ile ayrılır

Sağ kolon, malignite potansiyeli var

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Familial Adenomatous Polyposis

Otozomal dominant

Çok sayıda adenom genç yaşta gelişir

APC geninde mutasyon

>100 polip tanı için şart, binlerce polip olabilir

Robbins Basic Pathology

Robbins Basic Pathology

Poliplerin sayısı fazla ama morfolojik olarak sporadik adenomlardan farkı yok

Kolorektal kanser 30 yaş altında %100 gelişir

Profilaktik kolektomi

Başka neoplazilerle de ilişkisi var

• Gardner sendromu
  • Osteom, mandibula, kafa kemiği ve uzun kemikler
  • Epidermal kist
  • Dezmoid ve tiroid tümörleri
  • Diş anomalileri, çıkmamış ve artmış sayıda diş
• Turcot sendromu
  • Daha nadir
  • CNS tümörleri
  • 2/3 medulloblastom, APC gen mutasyonu var
  • 1/3 glioblastom, DNA tamir genlerinde mutasyon var
• FAP olup APC kaybı olmayan olgular
  • Base excision repair gene MUTYH mutasyonu var

Hereditary Nonpolyposis Colorectal Cancer

• Lynch sendromu
• Kolorektal, endometrium, mide, over, üreter, beyin, ince barsak, hepatobilier sistem, der,
• Daha genç yaşlarda ve sağ kolonda
• DNA tamir genlerinde germline mutasyon
  • MSH2 veya MLH1
  • HNPCC sendromunda bir mutant bir normal alle var
  • İkinci vuruş olduğunda mutasyon birikim hızı 1000 kat artar
    • Mutasyon ya da genetik defekt
  • Kısa tekrarların olduğu DNA sekanslarındaki hasar daha belirgin hale gelir ki bu durum klibikte mikrosatellit instabilte oalrak adalandırılır ve sendrom tanısında kullanılır

Adenokarsinom

• Gastrointestinal sistein en sık tümörü
• Moribidite ve mortalite nedeni
• Kanser ilişkili ölümlerin %15’I, akciğerden sonra ikinci sırada
• İnce barsak GIS’in %75’ini tutmasına rağmen tümörlerin çok azı burada oluyor
• İnsidans
  • 60-70 yaş arası pik yapıyor, <50 yaş %20
  • Erkeklerde daha sık
  • ABD, Kanada, .. Gibi gelişmiş ülkelerde daha sık
  • Hindistan, Güney Amerika ve Afrika’da 30x daha az
  • Japon insidansı giderek artıyor
• Lifli yiyeceklerin az, karbonhidrat ve yağların fazla tüketilmesi
• NSAID koruyucu etkisi olabilir

APC/β-catenin yolağı

Klasik multistep adenom-karsinom dizisi

Sporadik tümörlerin %80’i

APC mutasyonu erken bsamakta oluyor

Her iki allelde inaktif olmalı ki adenom gelişsin

APC yok

β-Catenin aktif

WNT durumundan bağımsız

WNT sinyali APC’yi inhibe eder

β-Catenin çekirdeğe girer

APC aktif

β-Catenin yıkılır

Robbins Basic Pathology

β-Catenin nükleusta aktif

cyclin D1 ve MYC transkripsiyonu, proliferasyona neden olur

TWIST ve SLUG eksorese olur

E-cadherin ekspresyonu baskılanır

Kontakt inhibisyon azalır

Robbins Basic Pathology

TP53 kolon tümörlerinin %70-80’inde mutant ancak adenomlarda yok

KRAS

10% <1cm

50% >1cm

50% adenokarsinom

SMAD2 ve SMAD4, TGF-β signaling effektörleri, normalde hücre siklusunu inhibe eder

TP53 ve diğerlerindeki fonksiyon kaybı kromozomal delesyonlarla olur

Bu yolakta kromozomal instabilite daha fazla

Epigenetiğin de rolü var

Robbins Basic Pathology

Mikrosatellit instabilite yolağı

DNA mismatch tamir eksikliği

Mutasyonlar birikir → mikrosatellit dengesizliğine neden olur

The microsatellite instability pathway

• Mutations accumulate in microsatellite repeats → microsatellite instability
  • Microsatellites typically are located in noncoding regions
  • Microsatellite sequences located in the coding or promoter regions of genes involved in regulation of cell growth
    • type II TGF-β receptor, uncontrolled growth
    • pro-apoptotic protein BAX, survival of abnormal clones

BRAF mutasyonu ve epigenetik susturulması

KRAS ve TP53 mutant değil

Robbins Basic Pathology

Adenokarsinom dağılımı

• Kolon boyunca dağılım gösterir
• Proksimal kolon
  • Polipoid, egzofitik
  • Obstrüksiyona neden olmaz
• Distal kolon
  • annular lezyonlar
  • Luminal daralma
  • obstrüksiyon

Robbins Basic Pathology

Robbins Basic Pathology

A: Well-differentiated adenocarcinoma. Note the elongated, hyperchromatic nuclei. Necrotic debris, present in the gland lumen, is typical.

Robbins Basic Pathology

Poorly differentiated adenocarcinoma forms a few glands but is largely composed of infiltrating nests of tumor cells.

Robbins Basic Pathology

Mucinous adenocarcinoma with signet ring cells and extracellular mucin pools

Poor prognosis

Robbins Basic Pathology

A: Lymph node metastasis

Glandular structures within the subcapsular sinus.

Robbins Basic Pathology

B: Solitary subpleural nodule of colorectal carcinoma metastatic to the lung.

Robbins Basic Pathology

C: Liver containing two large and many smaller metastases. Note the central necrosis within metastases.

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Autopsy Pathology: A Manual and Atlas

Appendiks tümörleri

• NET (Karsinoid)
  • En sık görülen tümör
  • İnsidental olarak bulunuyor
  • Daha çok appendiksin tip kısmında
• Düşük dereceli appendiks musinöz neoplazmları
  • Mukosel
    • Obstrükte appendiks içinde müsin göllenmesi
  • Müsinöz adenom, müsinöz karsinom
  • Psödokimsoma peritonei
  • Primer over tümörünü taklit eden metastaz

Tumors of Lower GI Tract

Serdar BALCI, MD

Polyps

• Most common in the colon
• May occur in the esophagus, stomach, or small intestine
• Most common neoplastic polyp is the adenoma
• Non-neoplastic colonic polyps
  • inflammatory, hamartomatous, hyperplastic

Those without stalks are referred to as sessile

As sessile polyps enlarge, proliferation of cells adjacent to the polyp and the effects of traction on the luminal protrusion, may combine to create a stalk

Polyps with stalks are termed pedunculated

Inflammatory Polyps

• Chronic cycles of injury and healing produce a polypoid mass made up of inflamed and reactive mucosal tissue
• Polyp that forms as part of the solitary rectal ulcer syndrome
  • Clinical triad of rectal bleeding, mucus discharge, and an inflammatory lesion of the anterior rectal wall
  • Impaired relaxation of the anorectal sphincter

Robbins and Cotran Pathologic Basis of Disease

Hamartomatous Polyps

Occur sporadically

Components of various genetically determined or acquired syndromes

Robbins Basic Pathology

Juvenile Polyps

• Most common type of hamartomatous polyp
• Children <5 years of age
• Located in the rectum
• Rectal bleeding, prolapse
• Sporadic juvenile polyps are usually solitary
• Autosomal dominant syndrome of juvenile polyposis 3-100 polyps
• Colectomy may be required
• Dysplasia occurs in a small proportion (mostly syndrome-associated)
  • Juvenile polyposis syndrome is associated with increased risk for the development of colonic adenocarcinoma
• Mucosal hyperplasia, transforming growth factor-β (TGF-β)

Pedunculated, smooth-surfaced, reddish lesions

<3 cm

Cystic spaces on cut sections

Dilated glands filled with mucin and inflammatory debris

Robbins Basic Pathology

Peutz-Jeghers Syndrome

Rare autosomal dominant disorder

Presence of multiple gastrointestinal hamartomatous polyps and mucocutaneous hyperpigmentation

Increased risk of several malignancies, colon, pancreas, breast, lung, ovaries, uterus, and testes

Germ line heterozygous loss-of-function mutations in the gene LKB1/STK11 are present in approximately half of the patients with the familial and subset of sporadic form

Intestinal polyps are most common in the small intestine, may also occur in the stomach and colon, rarely, in the bladder and lungs

Large and pedunculated

Lobulated contour

Arborizing network of connective tissue, smooth muscle, lamina propria, and glands lined by normal-appearing intestinal epithelium

Peutz-Jeghers polyp. Complex glandular architecture and bundles of smooth muscle help to distinguish Peutz-Jeghers polyps from juvenile polyps.

Robbins Basic Pathology

Hyperplastic Polyps

Common epithelial proliferations

Sixth and seventh decades of life

Decreased epithelial cell turnover and delayed shedding of surface epithelial cells, leading to a “pileup” of goblet cells

No malignant potential, must be distinguished from sessile serrated adenomas

Most commonly found in the left colon

Less than 5 mm in diameter

Smooth, nodular protrusions of the mucosa

Frequently multiple, in the sigmoid colon and rectum

Robbins Basic Pathology

Polyp surface with irregular tufting of epithelial cells

Robbins Basic Pathology

Robbins Basic Pathology

Tufting results from epithelial overcrowding

Epithelial crowding produces a serrated architecture when glands are cut in cross-section

Robbins Basic Pathology

Adenoma

Neoplastic mass lesion in the GI tract

Produce a mucosal protrusion, or polyp

Robbins Basic Pathology

Epithelial dysplasia

Small, often pedunculated polyps to large sessile lesions

No gender predilection

50% of adults living in the Western world beginning age 50

Precursors to colorectal cancer

Surveillance colonoscopy

fibromuscular stalk

Robbins and Cotran Pathologic Basis of Disease

Tubular adenoma with a smooth surface and rounded glands

Robbins Basic Pathology

Villous adenoma with long, slender projections that are reminiscent of small intestinal villi

Robbins Basic Pathology

The cytologic hallmark of epithelial dysplasia is nuclear hyperchromasia, elongation, and stratification

Changes are most easily appreciated at the surface of the adenoma, because the epithelium fails to mature as cells migrate out of the crypt

Robbins Basic Pathology

Sessile serrated adenoma

Lined by goblet cells without typical cytologic features of dysplasia. This lesion is distinguished from a hyperplastic polyp by involvement of the crypts

Most common in the right colon

Have a malignant potential similar to that of traditional adenomas

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Familial Adenomatous Polyps

Autosomal dominant disorder

Numerous colorectal adenomas by the teenage years

Mutations of the adenomatous polyposis coli gene ( APC )

>100 polyps is necessary for a diagnosis of classic FAP, and as many as several thousand may be present

Robbins Basic Pathology

Robbins Basic Pathology

Except for their remarkable numbers, these growths are morphologically indistinguishable from sporadic adenomas

Colorectal adenocarcinoma develops in 100% of patients with untreated FAP, often before age 30

Prophylactic colectomy

Neoplasia at other sites

• Gardner syndrome
  • osteomas of mandible, skull, and long bones
  • epidermal cysts
  • desmoid and thyroid tumors
  • dental abnormalities, including unerupted and supernumerary teeth
• Turcot syndrome
  • rarer
  • intestinal adenomas and tumors of the central nervous system
  • Two thirds of patients with Turcot syndrome have APC gene mutations and develop medulloblastomas
  • One third have mutations in one of several genes involved in DNA repair and develop glioblastomas
• Patients who have FAP without APC loss have mutations of the base excision repair gene MUTYH

Hereditary Nonpolyposis Colorectal Cancer

• Lynch syndrome
• Familial clustering of cancers at several sites including the colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, and skin
• Colon cancers tend to occur at younger ages than for sporadic colon cancers and often are located in the right colon
• Inherited germline mutations in DNA mismatch repair genes
  • MSH2 or MLH1
  • HNPCC inherit one mutated DNA repair gene and one normal allele
  • When the second copy is lost through mutation or epigenetic silencing, defects in mismatch repair lead to the accumulation of mutations at rates up to 1000 times higher than normal
  • Regions containing short repeating DNA sequences referred to as microsatellite DNA

Adenocarcinoma of Colon

• Most common malignancy of the gastrointestinal tract
• Major contributor to morbidity and mortality worldwide
• Small intestine, which accounts for 75% of the overall length of the gastrointestinal tract, is an uncommon site for benign and malignant tumors. Nearly 15% of all cancer-related deaths, second only to lung cancer
• Incidence
  • Peaks at 60 to 70 years of age, and less than 20% of cases occur before age 50
  • Males are affected slightly more often than females
  • Most prevalent in the United States, Canada, Australia, New Zealand, Denmark, Sweden, and other developed countries
  • 30x lower in India, South America, and Africa
  • Japan incidence is increasing
• Low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat
• NSAID may have a protective effect

The APC/β-catenin pathway

The classic adenoma-carcinoma sequence

80% of sporadic colon tumors

Involves mutation of the APC tumor suppressor early in the neoplastic process

Both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events, for adenomas to develop

No APC is present

β-Catenin is active independent of WNT status

WNT signal inhibits APC

β-Catenin enters nucleus

APC is active

β-Catenin is dectructed

Robbins Basic Pathology

β-Catenin is active in the nucleus

cyclin D1 and MYC transcribed for proliferation

TWIST and SLUG are expressed

They repress E-cadherin expression

Reduce contact inhibition

Robbins Basic Pathology

TP53 ?? 70% to 80% of colon cancers but is uncommonly affected in adenomas

KRAS

10% in <1cm

50% >1cm

50% in adenocarcinoma

SMAD2 and SMAD4, which are effectors of TGF-β signaling, normally inhibits cell cycle

Loss of function TP53 and others caused by chromosomal deletions, chromosomal instability in this pathway

Epigenetics

Robbins Basic Pathology

The microsatellite instability pathway

DNA mismatch repair deficiency

Due to loss of mismatch repair genes

• Mutations accumulate in microsatellite repeats → microsatellite instability
  • Microsatellites typically are located in noncoding regions
  • Microsatellite sequences located in the coding or promoter regions of genes involved in regulation of cell growth
    • type II TGF-β receptor, uncontrolled growth
    • pro-apoptotic protein BAX, survival of abnormal clones

Mutations in the oncogene BRAF and silencing of distinct groups of genes due to CpG island hypermethylation also are common in cancers that develop through DNA mismatch repair defects.

KRAS and TP53 typically are not mutated.

Robbins Basic Pathology

Adenocarcinoma distribution

• Distributed approximately equally over the entire length of the colon
• Proximal colon
  • polypoid, exophytic masses
  • that extend along one wall of the large-caliber cecum and ascending colon
  • rarely cause obstruction
• Distal colon
  • annular lesions that produce “napkin ring” constrictions and luminal narrowing
  • point of obstruction

Robbins Basic Pathology

Robbins Basic Pathology

A: Well-differentiated adenocarcinoma. Note the elongated, hyperchromatic nuclei. Necrotic debris, present in the gland lumen, is typical.

Robbins Basic Pathology

Poorly differentiated adenocarcinoma forms a few glands but is largely composed of infiltrating nests of tumor cells.

Robbins Basic Pathology

Mucinous adenocarcinoma with signet ring cells and extracellular mucin pools

Poor prognosis

Robbins Basic Pathology

Lymph node metastasis

Glandular structures within the subcapsular sinus.

Robbins Basic Pathology

B: Solitary subpleural nodule of colorectal carcinoma metastatic to the lung.

Robbins Basic Pathology

C: Liver containing two large and many smaller metastases. Note the central necrosis within metastases.

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Autopsy Pathology: A Manual and Atlas

Tumors of the Appendix

• NET (Carcinoid)
  • Most common tumor
  • Usually discovered incidentally
  • Distal tip of the appendix
• Low grade appendicial mucinous neoplasm
  • Mucocele
  • consequence of mucinous cystadenoma or mucinous cystadenocarcinoma
  • Invasion through the appendiceal wall can lead to intraperitoneal seeding and spread. In women, the resulting peritoneal implants may be mistaken for mucinous ovarian tumors
  • Pseudomyxoma peritonei