Pathologic Diagnosis of Gastric Epithelial Neoplasia 2008 년도 2 학기 의학과 석. 박사 공통과목 위장관의 외과병리

Introduction Diagnostic difference of gastric epithelial neoplasia between Japanese and Western pathologists We have same problems in diagnosis of gastric epithelial neoplasia in Korea, due to confused and complicated criteria between pathologists

Common Examples of Ambiguous Terminology Atypical cells, a few atypical cells, atypical glands, a few atypical glands A few dysplastic glands Focal atypia, focal suspicious atypical cells or glands, suspicious atypical glands, atypical gland proiliferation Suspicious carcinoma, dysplasia with focal suspicious cacinoma, suggestive adenocarcinoma, focal atypical cell infiltration, focal highly suggestive carcinoma, atypical glands, suggestive malignancy Carcinoma in situ

위 상피 증식성 병변의 등급체계 - 대한병리학회 소화기병리연구회 시안 - Grade 1: normal epithelium or atypical changes interpreted as regenerative process Grade 2: atypical changes interpreted as questionable dysplasia Grade 3: low grade dysplasia Grade 4: high grade dysplasia Grade 5: overt carcinoma 대한병리학회지 1997;31:

F1

F2

F3

F4

F8

F9

F11

F14

F16

F17

F18

F20

F22

F24

F26

F28

Western Classification Group 1. negative for dysplasia Group 2. indefinite for dysplasia Group 3. low grade adenoma/dysplasia Group 4. high grade adenoma/dysplasia Group 5. suspicious for invasive carcinoma Group 6. invasive carcinoma

Am J Surg Pathol 2000;24:

Gut 2000; 47:

Virchows Arch 2003; 442:99-106

J Gastroenterol 2001; 36:

Indefinite for Intraepithelial Neoplasia Neoplastic vs non-neoplastic –Cutting deeper levels of the block –Obtaining additional biopsies –After removing possible sources of cellular proliferation Native gastric mucosa: foveolar hyperproliferation –Irregular and tortous tubular structures with epithelial mucus depletion, high N/C ratio, loss of cellular polarity –Large, oval/round, hyperchromatic nuclei, prominent mitoses located near the proliferative zone Intestinal mucosa –Closely packed glands lined by cells with large, hyperchromatic, round or elongated, basally located nuclei –Nucleoli; inconsistent finding

Adenoma Circumscribed, benign lesions, composed of tubular and/or villous structures showing intraepithelial neoplasia (WHO) Limited to dysplasias of all grades of severity and of all architectural patterns that are circumscribed or localized and polypoid, meaning that they are elevated above the surrounding flat mucosa (AFIP) Include all gross types, i.e., flat, elevated, and depressed (Japan) Morphologically described as tubular, tubulovillous, or villous

Intraepithelial neoplasia (WHO) (Dysplasia, non-invasive neoplasia (NiN) Defined as an unequivocal neoplastic epithelial alteration Alterations coexisting with or reactive to an adjacent neoplasm (paracancerous lesion) and de-differentiated lesions with a potential for acquiring biologic features (local invasiveness, metastasis) typical of a fully developed adenocarcinoma (pre-cancerous lesion) Distinction from reactive or regenerative changes and from invasive carcinoma Three basic morphological features –Epithelial atypia –Abnormal epithelial differentiation –Disturbed mucosal architecture

GI Dysplasia Considered both a carcinoma precursor and a marker of high cancer risk for the site at which it is found Defined as unequivocal neoplastic epithelium, yet the specific criteria for making that determination are imperfectly defined Criteria include mix of architectural and cytologic features, all of which occur in different intensities in different epithelia that are given the same diagnosis –In colonic adenoma –In Barrett esophagus –In chronic atrophic gastritis –In ulcerative colitis The diagnosis of dysplasia is too subjective with less than optimal reproducibility to be as useful a marker as needed

Types of Gastric Dysplasia Adenomatous (Intestinal, type I) type: M/C –Composed of dysplastic-metaplastic intestinal epithelial cells, including the dominant undifferentiated or primitive cells, along with a group of differentiated cells such as goblet cells, Paneth cells, possibly absorptive cells, and endocrine cells –Precursor of well differentiated adenocarcinoma of intestinal type Foveolar (Gastric, type II) type –Composed of dysplastic cells resembling gastric foveolar and surface cells with atypical neutral mucin vacuoles –Associated with poorly differentiated adenocarcinoma of intestinal type Tubule neck (Globoid, type III) type –Precursor of diffuse type of gastric cancer

Grading of Gastric Dysplasia Two tier system (low and high grade) 핵의 길이가 세포길이의 1/2 이하 : low 핵의 길이가 세포길이의 1/2 이상 : high LD regresses in 38-75% and persists in 19-50%. HD regresses in 0-16% and persists in 14-58%. Progression to adenocarcinoma has been reported from 0-23% for LD (10 mo to 4 yr) and 60-85% for HD (4-48 mo).

Low-grade Dysplasia Elongated but uniform cells and their nuclei Nuclei are larger than normal and take up more of the cytoplasmic volume Nuclei are stratified, stratification is generally not higher than the basal half of the cells Increased mitosis, but usually not abnormal Hyperchromatic nuclei, but nor pleomorphic Small nucleoli Usually randomly dispersed goblet cells Architecturally, tubules of relatively uniform shape and size

High-grade Dysplasia More pleomorphic nuclei, larger nucleoli Stratification closer to full-thickness High nuclear to cytoplasmic ratio is the rule More irregular, more numerous mitosis More variation in cell size and shape Progressive lost of goblet cells: basophilic cytoplasm Progressive architectural disorganization with the formation of peculiarly shaped tubular structures, great variation in tubule size Compromise of the lamina propria so that the tubules are adjacent to one another, budding of tubules, and proliferation of dysplastic epithelial bridges across the tubular lumens resulting in cribriform foci

Carcinoma in situ Extreme form of high-grade dysplasia Characterized by marked cytologic atypia, with or without architectural complexity of the glands The glands proliferate and bud, resulting in an abnormal network of loop-shaped glands with anastomoses producing cribriform pattern The cytologic atypia is characterized by round cells with large, spherical, vesicular nuclei; irregularly clumped chromatin, and numerous large distinct and irregular nucleoli, considered by some as the hallmark of carcinoma Mitoses, which often are atypical, are frequently prominent.

Suspicious for Invasion Appropriate when the histological criteria for an invasive malignancy are equivocal Suggestive of true invasion –Isolated cells, gland-like structures, or papillary projections

Diagnosis of Carcinoma Western pathologists –Conventionally based on invasion, because of the ability of invasive lesions to metastasize Japanese pathologists –Basis of cytologic (variably sized and enlarged nuclei, rounded nuclei, loss of polarity, prominent nucleoli) and structural changes (complex budding or branching glands, back to back glands), irrespective of the aspect of invasion, as, pathogenetically, carcinoma arose from the epithelium and, logically, must be present before invasion has occurred

Drawback Western classification –Lead to discrepancies between the diagnosis of a biopsy specimen and that of the corresponding resected specimen, if attention is paid only to the aspect of invasion Japanese classification –If attention is paid only to cytological and architectural changes for the diagnosis of mucosal carcinoma, there is no distinction between noninvasive and invasive mucosal carcinomas; such a distinction may have prognostic significance and could be useful for research purpose

Causes of Diagnostic Errors in Gastric Adenocarcinoma Biopsies False negatives –Inadequate tumor sampling Tumor site difficult to biopsy Failure to recognized tumor cells because of necrosis or diffuse infiltration Insufficient and inadequately targeted biopsies False positives –Atypical regenerative epithelium aggravated by necrosis, granulation tissue, and crush artifact –Bizarre stromal cells beneath ulcers –Radiation and chemotherapy effects

* EMR of superficial early cancers of the upper GI tract is standard technique in Japan and is increasingly used in Western countries. Newer techniques of EMR allow removal of larger lesions en-bloc. These minimally invasive techniques, when applied correctly, allow safe and efficacious treatment in situations that would otherwise require major surgery.

Basis of EMR The overall risk of lymph node metastasis among patients with EGC is 2.7% and 18.6% as the cancer invades the mucosa and submucosa.

Location, size, gross appearance, histology, degree of differentiation, microscopic depth of tumor invasion, presence of ulceration, neoplastic involvement of the lateral and vertical margins, involvement of the lymphatic and/or blood vessels in the submucosa Report of the EMR specimens

Subdivision of early cancer of the GI tract according to depth of invasion M1: questionable invasion beyond the BM

Indications for EMR

Proposed expanded criteria for EMR and ESD for EGC Definition of curative ESD: resection in which the lateral and vertical margins of the specimen was free of cancer and absence of submucosal invasion deeper than 500 ㎛ from the muscularis mucosa, lymphatic or vascular involvement