Distinction of High-Grade Intraepithelial Neoplasia and Tubular Gastric Adenocarcinoma

Distinction of High-Grade

Intraepithelial Neoplasia and Tubular Gastric Adenocarcinoma

Michael Vieth¹and Manfred Stolte²

Introduction

When searching the literature for the definition of intraepithelial neoplasia (formerly dysplasia), we found it has been described as structural change of surface epithelium [1] and atypical mucosa limited to the epithelium [2]. The first international classifi- cation by Morson et al. [3] did not add anything significant to these criteria, leaving room for subjective interpretation.

WHO Definition of High-Grade Intraepithelial Neoplasia

In 2000, the World Health Organization (WHO) recommended to no longer use the term “dysplasia” but rather “intraepithelial neoplasia” throughout the gastrointestinal tract. This change has been suggested because the term dysplasia has been over- stressed in the past (Table 1) because of the weak descriptive nature of its definitions.

Also, the term dysplasia was used in part for early carcinomas [4].

The WHO classification [5] describes high-grade intraepithelial neoplasia in the stomach as a lesion with “glandular crowding and prominent cellular atypia. Tubules can be irregular in shape, with frequent branching and folding: there is no stromal invasion.” Mucin secretion is believed to be absent or minimized. Additionally, increased proliferative activity is present throughout the epithelium. According to the WHO classification, invasive adenocarcinoma is diagnosed whenever the tumor invades into the lamina propria or the submucosal layer. Also mentioned is that in bioptic diagnosis isolated tumor cells and glandlike and/or papillary projections are believed to help differentiate it from intraepithelial neoplasia.

109

1Institute of Pathology, University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany

2Institute of Pathology, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445 Bayreuth, Germany e-mail: vieth.lkpathol@uni-bayreuth.de

Are These Criteria Sufficient to Explain How to Make the Differential Diagnosis Between High-Grade

Intraepithelial Neoplasia and Invasive Mucosal Carcinoma?

The WHO definition of high-grade intraepithelial neoplasia is mainly based on the descriptive terms “branching and folding” of the glands. These two descriptive terms especially leave a lot of room for subjective interpretation. On the other hand, infiltra- tion of the submucosal layer by single neoplastic tubules is not described as “branch- ing of glands” but as a clear carcinoma even without the presence of single tumor cells (Fig. 1).

Worldwide differences in the diagnostic criteria of mucosal carcinomas mostly apply to bioptic diagnoses but not to (endoscopic) resection specimens and are prob- ably just a sign of uncertainty [6,7] rather than an expression of Japanese or Western points of view. Furthermore, some pathologists prefer the term high-grade intraep- ithelial neoplasia rather than adenocarcinoma for forensic reasons. Another reason seen by some pathologists is to avoid the patient’s health insurance changing the contract as a result of carcinoma diagnosis. It should be noted that in addition to morphological criteria there are also forensic and social criteria that are applied by some pathologists. This practice is unacceptable because it prevents relating clinical outcomes worldwide [8].

When analyzing the literature for follow-up studies on high-grade intraepithelial neoplasia up to the development of invasive gastric adenocarcinoma (Table 2), it becomes apparent that all these studies showed that within a few months invasive car- cinoma was present. Due to the very short time lag, this finding could be interpreted that these lesions were already carcinomas.

It is known that lesions designated as high-grade intraepithelial neoplasia do not differ much from invasive carcinoma concerning molecular and genetic changes. In our daily routine, the diagnosis of high-grade intraepithelial neoplasia is very rare.

Most of these lesions are already invasive carcinomas.

Table 1. Use of the term “dysplasia” taken from a selection of histological diagnoses

Dysplasia I–III Metaplastic dysplasia

“Proper gastric type” of dysplasia Hyperplastic dysplasia

Intestinal dysplasia Adenomatous dysplasia Microglandular dysplasia Anaplastic dysplasia Regenerative dysplasia Diffuse dysplasia Globoid dysplasia Strange dysplasia

Source: O. Stadelmann, personal communication

Differential Diagnosis

The differential diagnosis of intraepithelial neoplasia and early invasive carcinomas includes pseudoinvasions (cohesive type as in gastritis cystica profunda; diffuse type as in NHL-MALT-lymphoma with scattered remaining epithelial structures imitating invasive epithelial growth). Other differential diagnoses include neuroendocrine tumors and reactive changes as in chemical reactive gastritis (Fig. 2); especially, NSAID/ASA-induced lesions should be excluded. The endoscopic findings should be consistent with the neoplasia diagnosis and should be carefully reviewed.

Sometimes criteria are difficult to interpret; therefore, a so-called matrix diagnostics with biopsies far from the questionable lesion from antrum and corpus (two each) should be taken to avoid overdiagnosis of a reactive lesion toward a neoplasia in case the patient is Helicobacter pylori negative, which would point more toward a reactive lesion.

How Can High-Grade Intraepithelial Neoplasia Be Reliably Distinguished from Invasive Adenocarcinoma?

Clinically, the distinction of gastric high-grade intraepithelial neoplasia and mucosal carcinoma does not play a role because both lesions after careful staging do require endoscopic resection [6], and most lesions should be already regarded as mucosal car- cinomas rather than high-grade intraepithelial neoplasia.

An exact description of the term invasion is lacking in the European and Ameri- can literature. In the WHO classification [5], invasion is defined through the presence of expansion of atypical cells through the basal membrane or even expansion through anatomical structures (e.g., muscularis mucosae in colorectal tumors). In Japan, pathologists use structural change of nuclei, hyperchromasia, anisonucleosis, etc., for the diagnosis of “malignancy” [6]. Precise descriptions of expansive growth of gastric neoplastic lesions are most available exclusively from Japanese authors [9–11]

(Fig. 3).

In the European literature up until now, only one German author [12] ever tried to find an exact description of invasion that is in line with the criteria and findings from Table 2. Results from follow-up studies of high-grade intraepithelial neoplasia up to invasive gastric adenocarcinoma

Author Year n HGIEN Æ Ca in % Months

Saraga et al. [15] 1987 21 81 4

Lansdown et al. [16] 1990 13 85 5

Rugge et al. [17] 1991 8 75 4

Fertitta et al. [18] 1993 31 81 5

Di Gregorio et al. [19] 1993 10 60 11

Rugge et al. [20] 1994 18 78 9

Kokkola et al. [21] 1996 3 67 18

Mean: 78% 8

HGIEN, high-grade intraepithelial neoplasia (formerly high-grade dysplasia); Ca, carcinoma

Japan (Tables 3, 4). According to Borchard, in carcinomas the expansion pattern is unique. The malignant epithelium shows a so-called primarily lateral intertubular expansion deriving from the proliferation zone within the mucosa (Figs. 4, 5). Expan- sion of atypical cells through the basal membrane, spreading of single tumor cells, and stromal fibrous reaction are criteria for more advanced lesions. The presence or absence of basal membranes correlates with the grading of the tumor. Well- differentiated adenocarcinomas are capable of generating basal membrane compo- nents by the tumor itself. Only poorly differentiated or diffuse carcinomas show a loss of basal membrane synthesis, mostly due to mutations of E-cadherin. Frequently this mutation can be detected in diffuse gastric carcinomas with loss of adhesion among the tumor cells. This complicates the diagnosis: is there a disruption of the basal membrane or a loss of the basal membrane? then the lesion shows definitively invasion but, as already pointed out, this criterion is not always present in well-differentiated adenocarcinomas.

Normal gastric mucosa Gastric adenoma G1 gastric adenocarcinoma Fig. 3. Three-dimensional microstructure of normal gastric mucosa, adenoma, and well- differentiated (G1) gastric adenocarcinoma. (Modified after Refs. [10,11])

Table 3. Criteria of expansion in adenomas and early gastric carcinomas besides cytological criteria of malignancy

Adenoma Carcinoma

Type of expansion Tubular Villous Tubular Diffuse

Septae (+) - - -

Intratubular expansion + ++ - -

Superficial lateral expansion + + - -

Luminal expansion + ++ (+) -

Intertubular vertical expansion + + (+) -

Intertubular lateral expansion - - ++ ++

Undermining growth pattern - - + +

Compression and destruction - - + +

Loss of basal membrane - - (-)+ ++

Source: Modified from Refs. 12, 22

Table 4. Cytological and structural criteria of high-grade intraepithelial neoplasia and invasive adenocarinoma

High-grade

Criterion intraepithelial neoplasia Invasive carcinoma

Architecture Irregular Branching, anastomoses

Rare: single tumor cells

Proliferation zone Whole gland Whole gland

Epithelial expansion Surface epithelium Also underneath surface epithelium

Epithelial differentiation None None

Foveolar epithelium None None

Nuclear layer in rows 2–5 Changing within one gland

Size of nucleus Enlarged Vesicular

Nucleoli Some Prominent, possible:>1

Source: Modified from Refs. [12, 22]

Fibrous stromal reactions around neoplastic tubules is an important criterion, but these are often detected in lesions that have already infiltrated the submucosal layer.

This stromal fibrous reaction is most prominent in the submucosal and subserosal layer. Therefore, mucosal carcinomas almost never show such a fibrous reaction.

Within the muscularis propria, the reaction is less dominant [13]. Fibroblasts of fibrous peritumoral reaction are less differentiated than peritubular fibroblasts [14].

Mucosal lesions of diffuse gastric carcinomas very rarely show a fibrous stromal reac- tion. The leading finding in well-differentiated mucosal carcinomas is, according to Borchard [12], the presence of a nonsuperficial lateral intertubular expansion that shows an abnormal branching of foveolae with tubular fissions; this results in a compression of the adjacent tissue (glands, capillaries), consecutive atrophy of neigh- boring glands, and stopping of regular cell movements during differentiation and pro- liferation. If stem cells of the gastric mucosa that are located very close to the surface (in the colorectum close to the base of the mucosa) are destroyed by the tumor, no further regeneration can be detected. Because of the lack of regeneration, subepithelial growth of cancerous tubules, and compression of capillaries, superficial destruction can occur in mucosal carcinomas. In adenomas with a regular vertical growth pattern, no erosion or superficial destruction can be observed.

Clinical Relevance

From a clinical point of view, the distinction of high-grade intraepithelial neoplasia and mucosal gastric carcinoma is without consequence because the diagnosis of high- grade intraepithelial neoplasia should always first lead to a (diagnostic) endoscopic resection. The final diagnosis could then be made on the basis of the resection spec- imen: high-grade intraepithelial neoplasia or mucosal adenocarcinoma. In routine practice, it should be noted that the diagnosis of high-grade intraepithelial neoplasia is very rare because most cases have already progressed to mucosal adeno- carcinoma.

References

1. Oehlert W, Keller P, Henke M, Strauch M (1979) Gastric mucosal dysplasia: what is its clin- ical significance? Front Gastrointest Res 4:173–182

2. Grundmann E, Schlake W (1982) Histological classification of gastric cancer from initial to advanced stages. Pathol Res Pract 173:260–274

3. Morson BC, Sobin LH, Grundmann E, et al (1980) Precancerous conditions and epithelial dysplasia in the stomach. J Clin Pathol 33:711–721

4. Lewin KJ, Appelman HD (1995) Tumors of the esophagus and stomach. In: Atlas of Tumor Pathology, Third Series, Fascicle 18. Armed Forces Institute of Pathology, Washington, DC

5. Hamilton SR, Aaltonen LA (eds) (2000) WHO classification. Tumors of the digestive system.

IARC Press, Lyon

6. Schlemper RJ, Riddell RH, Kato Y, et al (2000) The Vienna classification of gastrointestinal epithelial neoplasia. Gut 47:251–255

7. Stolte M (1999) Diagnosis of gastric carcinoma: Japanese fairy tales or Western deficiency?

Virchows Arch 434:279–280

8. Stolte M (2003) The new Vienna classification of epithelial neoplasia of the gastrointestinal tract: advantages and disadvantages. Virchows Arch 442:99–106

9. Hattori T (1985) Histological and autoradiographic study on development of group III lesion (dysplasia grade III) in the stomach. Pathol Res Pract 180:36–44

10. Takahashi T, Iwama N (1984) Architectural pattern of gastric adenocarcinoma—a 3- dimensional study. Virchows Arch (Pathol Anat) 403:127–134

11. Takahashi T, Iwama N (1985) Three-dimensional microstructure of gastrointestinal tumors.

Gland pattern and its diagnostic significance. Pathol Annu 20:419–440

12. Borchard F (2000) Forms and nomenclature of gastrointestinal epithelial expansion: what is invasion? Verh Dtsch Ges Pathol 84:50–61

13. Othani H, Sasano N (1983) Stromal cell changes in human colorectal adenomas and carci- nomas. Virchows Arch Pathol Anat 401:209–299

14. Yao T, Tsuneyoshi M (1993) Significance of pericryptal fibroblasts in colorectal epithelial tumors: a special reference to the histologic features and growth patterns. Hum Pathol 24:

525–533

15. Saraga EP, Gardiol D, Costa J (1987) Gastric dysplasia. A histological follow-up study. Am J Surg Pathol 11:788–796

16. Lansdown M, Quirke P, Dixon MF, et al (1990) High-grade dysplasia of the gastric mucosa:

a marker for gastric carcinoma. Gut 31:977–983

17. Rugge M, Farinati F, Di Mario F, et al (1991) Gastric epithelial dysplasia: a prospective mul- ticenter follow-up study from the Interdisciplinary Group on Gastric Epithelial Dysplasia.

Hum Pathol 22:1002–1008

18. Fertitta AM, Comin U, Terruzzi V, et al (1993) Clinical significance of gastric dysplasia:

a multicenter follow-up study. Gastrointestinal Endoscopic Pathology Study Group.

Endoscopy 25:265–268

19. Di Gregorio C, Morandi P, Fante R, et al (1993) Gastric dysplasia. A follow-up study. Am J Gastroenterol 88:1714–1719

20. Rugge M, Farinati F, Baffa R, et al (1994) Gastric epithelial dysplasia in the natural history of gastric cancer: a multicenter prospective follow-up study. Interdisciplinary Group on Gastric Epithelial Dysplasia. Gastroenterology 107:1288–1296

21. Kokkola A, Haapiainen R, Laxen F, et al (1996) Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: a follow up study. J Clin Pathol 49:979–984

22. Borchard F, Heilmann KL, Hermanek P, et al (1991) Definition und klinische Bedeutung der Dysplasie im Verdauungstrakt. Pathologe 12:50–56

Fig. 2. Regenerative epithelium in chemical reactive gastritis of antrum mucosa with pleo- morphic nuclei and even mitoses are seen; slight change of the architecture of the glands. Note basal orientation of nuclei. Hematoxylin and eosin.¥100

Fig. 1. Initial infiltration of the submucosal layer by a well-differentiated gastric adenocarci- noma without presence of single tumor cells or branching or folding

Color Plates

Fig. 5. Early well-differentiated gastric adenocarcinoma showing malignant single cells that expand downward through adjacent stromal tissue

Fig. 4. Pattern of expansion in early mucosal carcinoma showing lateral intertubular expansion with initial discontinuing growth pattern with compression of neighboring glands and capil- laries. Later destructions of the surface epithelium in the presence of erosions can be observed