Elevated Early Gastric Carcinoma.Differential Diagnosis as Regards Adenomatous Polyps

Path. Res. Pract. 164,316-33° (1979) Institute 0; Pathology, Bispebjerg Hospital, Copenhagen, Denmark

Elevated Early Gastric Carcinoma. Differential Diagnosis as Regards Adenomatous Polyps A.JOHANSEN

Summary Differential diagnostic problems between gastric carcinomas and precancerous lesions with severe dysplasia have become more perceptible with the increasing number of resected early carcinomas. Although such problems come up for all macroscopic and histologic types of gastric cancer they are particularly marked between early carcinomas of the elevated type and adenomatous polyps. Elevated early carcinomas are usually highly differentiated adenocarcinomas with a morphology which often reminds of adenomas. But sometimes the carcinomas also demonstrate convincing signs of being developed from adenomas. The criterion of distinction between intramucosal carcinomas and adenomas is invasion through the basal membrane, often difficult to evaluate. The morphological relation between elevated early gastric carcinomas and adenomas and the criterion of distinction between them were studied in 20 early gastric carcinomas of the Japanese types I and Ira, 6 intramucosal and 14 submucosal all highly differentiated adenocarcinomas, and in 42 polyps, of which 5 were of the adenomatous type. All lesions were taken from resection specimens. Among the carcinomas 5 demonstrated convincing signs of being malignant transformed adenomas. In addition, 6 carcinomas had a morphology which more or less reminded of adenomas, but their genetic origin was more uncertain. Nine carcinomas revealed no sign of an adenomatous origin. Among the 5 polyps diagnosed as adenomas 2 revealed an extraordinary degree of severe dysplasia which caused uncertainty on the benign diagnosis. The rest of the polyps were without dysplasia. The significance of invasion through the basal membrane as an indispensable factor of distinction between adenoma and carcinoma in the stomach is discussed. It is concluded that the degree of dysplasia can be so severe and the invasion so difficult to evaluate that the classification of some few tumours depends on the subjectivity of the single pathologist.

Four of the tumours, 2 adenomas and 2 intramucosal carcinomas, having a remarkable macroscopic appearance like a large mucosal fold are especially mentioned. Their relation to gastric mucosal prolaps is discussed. Furthermore, a tumour apparently demonstrating only a moderate degree of dysplasia, but even so setting up metastases is mentioned in detail.

Early Gastric Cancer and Polyps . 3 I 7

Introduction The increasing frequenc y of gastric cancer diagnosed at its earl y stage has caused that problems about gastric carcinom a are presented in a new way to the pathologist. Examination of the ordinary adva nced carcinoma concentrates mainl y on classification and grading because the diagnosis itself is a matter of course. In contrast to this the very diagnosis carcinoma is important when early tumours are examined because obvious macroscopic signs of malignancy often are absent and , in addition, the histological examination can reveal a picture whi ch makes distinction from pr ecancerous lesions difficult. These problems are present for all histological types of early gastric cancer, but particularly the highly differentiated adenocarcinomas can be difficult to deliminate from pure dysplastic changes when the carcinoma is of the intramucosal variant. Highly differentiated adenocarcinomas are found in all groups of the ordinar y Japanese classificat ion of early carcinom as, but make up a special high percent of the elevated carcinomas of type I and IIa (Elster et aI., 197 5; Joh ansen, 1976 ; Rosch and Koch, 1976 ; Nag ayo, 1978). Since these carcinom as ofte n have an appearance reminding of polyps the diagnostic problems are accentu ated . It is the aim of thi s work to pr esent and discuss the diagnostic problems of elevated lesions in the stomach as met by the pathologist.

Material andMethods Among 90 early gastr ic carci nomas exa mined in the department dur ing the last 15 years 2 0 were of the eleva ted ty pe. They were found in 19 resection specimens. Six were of the intramucosal typ e, the rest of th e submucosal type. In th e same specimens there were 9 polyps. Twenty-six polyps were found in a collection of adv anced gastric carcinoma specimens from th e same period. In addition, 7 polyps came fr om 4 specimens, years ago resected because of these polyps. The total numb er of elevated carcinomas and benign polyps studi ed were consequentl y 20 and 42 respectively, an d the resection specimens in which they were located were available in all cases. Tw o of the tumours, I carcino ma and I adenom a, were primarily removed by endoscopy, but since malignancy and suspicio of malignancy respectively were histologically diagnosed resections were late r carrie d out. D ur ing recent year s an increasing numb er of small polyps removed by endoscopy has been examined . They are not included in the mat erial. All specimens were paraffin embedd ed in ordinary way and sections were stai ned by H &E, va n Gieson, PAS, Alcia n blue, and Co lloida l Ir on. Denotations Th e elevated carcinomas were all of the ty pes I or II a according to th e Japanese

3 I 8 . A. Johansen classification. A type I carcinoma is an early carcinoma where "the protrusion of the tumour into the lumen is eminent". A type IIa carcinoma is one of the subtypes of the second group of carcinomas in the classification. The tumours of that group are characterized by "an inconspicuous unevenness of the surface", and the IIa subtype demonstrates a slightly elevated surface. The two tumours (type I and IIa) are usually looked upon as different sizes of the same form. The difference is that the elevation of type IIa must not be higher than the thickness of the mucosa. Gastric polyps have been the object of extensive investigations but a classification upon which all agree is not available. However, most reports reflect a simple two-type grading of polyps, the neoplastic and the non-neoplastic. The first type is most often equal to adenomas although this name sometimes is used in other meanings. The nonneoplastic polyps are designated hyperplastic, hyperplasiogenous, inflammatory, or reactive - the first mentioned being the most common name. According to most authors dysplasia only develops in the neoplastic adenomas. The differences in nomenclature can topically be managed by dividing the polyps into two groups: polyps with and without dysplasia. Gastric epithelial dysplasia is defined as changes consisting of varying degrees of the following three features: cellular atypia, abnormal differentiation, and disorganized mucosal architecture. Dysplasia in different precancerous lesions as e.g. polyps is considered the best histological marker for carcinoma development although the course is not fully elucidated.

Results The 14 submucosal elevated carcinomas (Table I) caused naturally no problem concerning the diagnosis invasive carcinoma. However, 2 of them demonstrated only severe dysplasia in their intramucosal part like adenomas and were diagnosed as carcinomas solely because of the penetration through the muscularis mucosae. Other four of the submucosal carcinomas had a building also reminding of adenomas but convincing proof of this origin could not be established. The last 8 submucosal elevated tumours were positively without any sign of adenomatous origin. The 6 intramucosal carcinomas were more illustrative. Three of them exhibited obvious signs of being malignant transformed adenomas. The greatest part of the lesions had a rather equal building with pits covered by Table

r.

The genesis of elevated early gastric carcinomas with reference to adenomas

Early Gastric Cancer and Polyps

3 19

Fig. 1. Top: Polypoid early gastric cancer originating from a pedunculated tubular adenoma. HE ; X J. Below left : One of the two separated areas with invasion through the basal membrane in the tumour. HE; X 60. Below right: The inva sive area. HE; X 250.

po

A. Joha nsen

Fig. 2 . Top: Fold-like early carc inoma originatin g In a large sessile pylori c adenom a (case I in th e text ). The duodenum is to the left . HE; X 4. Below left: A detail of the carcinomatous part (indicated by the smallest ar row). HE ; X 1 0 0 . Below right: A detail from the adeno matous part (indicated by the largest arr ow). HE ; X 100.

Earl y Gastric Cancer and Polyps . 32 I

Fig. 3. Sessile adenoma with areas demonstrating very severe dysplasia but without penetrat ion of the basal membrane of the glands and pit s. Left: HE; X 3. Right: HE: X

120.

Fig. 4. Left : A hyperplastic polyp. H E ; X 25. Right: A hyperplasiogenous polyp. HE: X 1 0. Both without dysplasia.

32 2 . A. Johan sen

Fig. 5. Top left : Fold -like prepyloric carcinoma (case 3 in the text) . Top right: A section throu gh the fold indicated by the open arro ws. A small villous adenoma is seen on the duodenal side of the fold . HE; X 3. Below left : Area representative for the discontinuous changes seen all over the fold. HE; X 40. Below right : Transition into a low differ entiated carcinoma with signet ring-cells. Position indicated by the arrow. HE; X 40.

Early Gastric Cancer and Polyps . J2 3

Fig. 6. Top left: Fold-like prepyloric adenoma (case 4 in the text). Top right : A section th rough the fold. The duod enum is to the left . HE ; X 3. Below: The area indicated by the arrow. The neck region exhibits a severe mucosal disorganization with a moderate cellular atypia. Note the normal pylor ic glands above the muscularis mucosae. HE; X 40.

3 24 . A. Johansen

Fig. 7. An unusual adenoma-like tumour (case 5 in the text) occupying the greatest part of pars pylorica. Duodenum downwards. The split to the right is artificial. The white line indicates the position of the section below. The tumour had more the appearance of hyperplastic polyps than of adenomas . There was only slight dysplasia, but the patient died of metastases from the tumour. Below: HE; X 10.

Early Gastric Cancer and Polyps . 32 5

a stratified epithelium demonstrating moderately or severely cellular atypia. Moderately atypical nuclei were elongated, darkly stained, uniform of size and without prominent nucleoli and mostly situated in the lower half of the cells. Severe atypical nuclei were more oval or round, not so darkly stained and had a more varying size and prominent nucleoli. The nuclei were often pushed forward in the cell. Two of the lesions were based on intestinal metaplastic epithelium. The abnormal differentiation was revealed by a complete disappearance of Paneth cells and a gradual loss of goblet cells which in the more severe grades of dysplasia had disappeared completely. When the origin of the lesion was original gastric foveolar epithelium, a loss of the ability to secrete PAS-positive mucin was noticed. The disorganization of the epithelium was revealed as a dos-a-dos arrangement of the pits and a more or less disappearance of the original glands which were replaced by cystic dilatated glands covered by an epithelium with more or less marked nuclear atypia. The way of transformation of these 3 primarily adenomatous tumours into carcinomas differed from case to case. One case (Fig. I) was composed of glands and pits demonstrating a very severe dysplasia, particularly an expressed cellular atypia, but penetration of the basal membrane could only be registered in 2 pits located in different areas of the tumour. The second case (case I - vide infra) (Fig. 2) showed the picture of a large sessile adenoma in by far the greatest part. The glands were covered with cells exhibiting most often moderate atypia. Only in a single area the tumour transformed rather abruptly into an intramucosal carcinoma. And the third case (case 3 - vide infra) (Fig. 5) revealed a discontinuous extension. The most conspicuous dysplastic feature was an abnormal differentiation and disorganization of the neck region in the pits found in separated places. The diagnosis carcinoma was uncertain except for one single area where the dysplastic pits transformed into a low differentiated carcinoma with some signet ring-cells. Two other intramucosal carcinomas were probably also of adenomatous origin, but not so obviously. The last carcinoma in the group revealed no sign of being a former adenoma. The 5 adenomas were diagnosed among 42 benign polyps (Table 2). They revealed a picture as described above, but no sign of invasion was found. Particularly in 2 cases (Fig. 3) the dysplasia was very severe and all the 3 features, cellular atypia, abnormal differentiation, and disorganized architecture, had reached heavy degrees, but anyway, the many sections did not reveal penetration trough the basal membrane. A third tumor had mainly the appearance of a hyperplastic polyp composed of elongated foveolae with a heavy mucous secretion and with dilatated glands covered

p6 . A. Johansen Table

2.

The degree of dysplasia in

No dysplasia

Elevated benign gastric tumors Adenomas Hyperplastic/ hyperplasiogenous polyps

o

37

42

benign elevated gastric tumours

Degree of dysplasia slight moderate severe 2

2

o

o

by an equal epithelium below them, but in the middle of the elevation was an area of intestinal metaplasia where the pits undoubtly revealed a slightly dysplastic change. Except for the just mentioned case no dysplasia was revealed in any of the 37 hyperplastic polyps and consequently no differential diagnostic problems towards carcinoma came up. The polyps roughly felt into two groups (Fig. 4): those composed of hyperplastic foveolae having more or less replaced the glands of the mucosa, and those also exhibiting marked cyst formation and usually being larger. These correspond to what has been called hyperplasiogenous polyps by Elster (r974). Concerning the nature of the mucosa from which the elevated tumours arose and which was found to surround them at the time of resection both the carcinomas and the adenomas were intimately related to a severe metaplastic mucosa except for 3 cases (r carcinoma and 2 adenomas). These were localized in a mucosa which revealed only very little intestinal metaplasia and only slight degrees of inflammation and atrophia outside the tumour. All lesions were localized in the pyloric part except for one type I carcinoma which was found r 3 em from the pyloric ring on the posterior wall. However, in this case the total resection specimen, which was rather large, demonstrated excessive metaplasia in its whole extension and no body mucosa at all was found. This was also the case for 3 other specimens with prepyloric tumours, but in the rest it was possible to demonstrate the border between pyloric and body mucosa. However, in all cases a sevre atrophic body gastritis was present. The macroscopic appearance of the elevated tumours varied. The shape of the carcinomas was polypoid, nodular hemispheric, or - particularly for the type IIa lesions - warty or papuloid. There were no fundamental differences between the adenomatous polyps and the carcinoma. Generally the tumours were of a sessile type and when a stalk was present is was usually broad. The hyperplastic polyps were either small nodules with a

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diameter of a few millimetres or larger lesions having more the appearance of a classical polyp, but in no case the morphology of a typical pedunculated colon adenoma was present. In the material were 5 lesions, 3 carcinomas and 2 adenomas, which exhibited a macroscopic appearance quite different from the classical morphology of common type I and type IIa lesions and also from the ordinary polyps. Four were nearly equal, fold-like, the 5th differed from both the four and all the other ones. The 4 fold-like lesions all had a morphology which best can be described as a mucosal fold pointing towards the duodenum and not sharply demarkated from the surroundings. The folds were rather thin with a trapeziumor fan-like appearance, their base-line being shorter than the top. Sagittal sections demonstated traditional polyp-like pictures and the base-lines of the folds were long enough to permit that several such sections for embedding could be made. Since the appearance was unusual and to my knowledge not reported a short note of each of the 4 casesshall be given: Case I,' (Fig. 2). A 84-years old woman, Billroth II resected for a malignant ulcer of pure signet ring-cell type localized at the upper part of the small curvature. In the prepyloric part a fold-like lesion was found. The fold was about 3 em high and at the base and the top 2 and 3 em broad respectively. Microscopy revealed an intramucosal carcinoma developed in an adenoma of tubule-villous character. As mentioned before the adenoma occupied the whole macroscopic fold. Case 2: A 75-years old man, Billroth II resected for 3 synchronous type I lesions, an intramucosal and two submucosal carcinomas localized in the upper part of the specimen. The entire pyloric channel was occupied by a humphy lesion which like a fold extended across the pyloric ring in the resected specimen. The height of the fold was about 2 em and the whole area 4 by 5 cm. Microscopy revealed an adenoma with moderately dysplastic changes of the foveolae and cystic dilatation of the underlying glands. Case 3,' (Fig. 5)' A 45-years old woman, Billroth I resected for a corporic ulcer on the small curvature. Distally in the pyloric channel was a transverse fold-like lesion, the height of which was 2 em. It projected towards the duodenum. On the distal side of the fold was a small globe-like lesion having the appearance of a villous adenoma. As mentioned, microscopy demonstrated an adenoma which in serveral separated areas transformed into a rather low differentiated carcinoma and at the bottom of the fold into a carcinoma of signet ring-cell type. The carcinoma was an intramucosal one. 22 Path. Res. Pract. Vol. 164

328 • A. Johansen

Case 4: (Fig. 6). A 52-years old woman resected for a prepyloric adenoma having the appearance of a fold, 21/ 2 ern of height. On the proximal side of it was a round, slightly depressed erosion, I cm of diameter. On the distal part was seen a small nodule about 1/2 em of diameter. The microscopy revealed an adenoma with slight to moderate dysplasia accentuated at the depressed area. First and foremost there was a disorganization of the neck regions of the pits but also a moderately cellular atypia. The mentioned 5th case revealed an unusual history and a rare histologic building. Case 5: (Fig. 7). A 8o-years old woman, Billroth II resected for a large humphy tumour occupying the greatest part of the antrum and the pyloric channel. The tumour had the appearance of several nodules or sessile polyps situated in close connection to each other. The single nodules were most marked at the periphery of the tumour and merged into each other in the centre. Their largest height was I em. The entire specimen was sectioned, 58 blocks were made. The histological picture was rather uniform. The mucosa was thickened and looked more hyperplastic than neoplastic, areas of ordinary and metaplastic epithelium alternated and both sorts of epithelium revealed expressed elongation of the foveolae or tubes. The non-metaplastic foveolae were heavily mucous secreting and the number of goblet cells in the metaplastic foveolae was not reduced. There were several transition forms between ordinary and fully matured metaplastic epithelium. There was a very slight nuclear atypia in most areas and hardly a moderate degree of dysplasia was reached in the middle of the tumour. There was no part in which the dysplasia could be called severe according to the common criteria. A rather uncertain diagnosis of an adenoma-like lesion with at the maximum moderate dysplasia was made. However, about one year after the operation the patient developed a cutaneous tumour in the loin and a few months later she died. Autopsy revealed several liver metastases. These and the cutaneous tumour demonstrated a histological picture equal to the primary tumour in the stomach.

Discussion Invasion through the basal membrane of the glands and pits is a condition of the diagnosis carcinoma. Poorly differentiated gastric carcinomas as e.g. the signet ring-cell type cause no problems neither for the early stage. The tumour cells are situated singularly in the lamina propria and even the smallest carcinoma can be diagnosed with certainty. Highly differrentiated adenocarcinomas can, on the other hand, cause problems when diagnosed in the early stage. Particularly when such carcinomas are of the

Early Gastric Cancer and Polyps • 329

elevated type real differential diagnostic problems towards dysplastic adenomatous polyps can arise. The mentioned three features of dysplasia can separately or simultaneously attain such degrees of severity in an adenoma that the diagnosis carcinoma seems to suggest itself, but stromal invasion is still difficult to assess. If the severely dysplastic glands seen in intramucosal lesions difficult to classify are the original ones, which grow in an disorganized way showing severe nuclear atypia, true invasion is not present. If some of the dysplastic glands are the result of ligation of bulges from the original ones invasion is present. It can be added that glands situated deep in advanced, highly differentiated adenocarcinomas isolated regarded can be interpreted as dysplastic, although they in fact represent invasion. In a report concerning dysplastic changes of gastric epithelium Nagayo (1972) mentioned 5 degrees. It is said about the most severe degree (group 5): "Group 5 defined as 'obvious carcinoma' has histological characteristics indicating carcinoma both from cytological and structural abnormalities, even though infiltrative growth of the tissue is still not prominent ... ". There are undoubtly cases where the distinction between severe dysplasia and carcinoma is so questionable that the subjectivity of the single pathologist will dominate the diagnosis . The situation is not unique for the stomach; it is well-known in other regions where carcinomas develop from glandular epithelium. Comparison with the conditions in the colon is obvious. It is generally accepted that transformation of colon adenomas into invasive carcinomas in practice requires a penetration of the muscularis mucosae. This view is probably based on experience, but it seems to apply. According to the definition of early gastric carcinoma the muscularis mucosae is of no importance and intramucosal type I carcinomas with lymph node metastases have been described (Nagayo, 1965) although seldom. This fact can support the view of Elster (1974) that analogies between colonic and gastric polyps are unfortunable. On the other hand, some of the sessile stomach adenomas have a striking similarity with the sessile colon adenoma, and considering that most gastric carcinomas arise from a totally intestinalized mucosa (Morson, 1955) it seems a little difficult to understand that the two adenomas colonic and gastric - should be principally different what in a way is suggested by designating the gastric ones "border-line lesions" (Elster, 1976). Concerning the unusual form of the four mentioned fold-shaped tumours it is difficult to state whether the fold has caused the adenoma/carcinoma or whether the sequence has been the opposite. The condition reminds of stomach mucosal prolaps which is not so seldom seen (Jansen,

330 . A. Johansen

1974). According to Alnor et al. (1962) this condition can be divided into a pure mucosal, a fibrous, and a muscular variant. The above mentioned cases had close similarities with the mucosal form. It is often seen related to duodenal ulcer and is probably caused by chronic gastritis. In none of the mentioned 4 cases duodenal ulcer was present. The attention has been drawn against these unusual tumours because they owing to the shape is difficult to diagnose by endoscopy. The 5th mentioned case shows that severe dysplasia is not an indispensable precursor for carcinoma. In this case the carcinoma seems to have arisen directly from slight to moderate dysplasia which consequently may be interpreted as a precancerous marker - although seldomly registered.

References Alnor, P. Ch., Kricke, E., and Werner, H. ].: Der Magenschleimhautprolaps. Urban & Schwarz enberg, Miinchen (1962) Elster, K.: A new approach to the classification of gastric polyps. Endoscopy 6, 44-47 (1974) Elster, K.: Histologic Classification of Gastric Polyps. In: Current Topics in Pathology, Ed. by B. Morson, Vol. 63, pp. 77-9J. Springer-Verlag, Berlin-Heidelberg-New York (1976) Elster, K., Kolaczek, F., Shimamoto, K., and Freitag, H.: Early Gastric Cancer - Experience in Germany. Endoscopy 7, 5- 10 (1975) Jansen, H. H.: Magen. In: Organpathologie, Ed. by W. Doerr, Vol. II, pp. 4-51, 4-73. Thieme, Stuttgart (1974) Johansen, Aa.: Early Gastric Cancer. In: Current Topics in Pathology, Ed. by B. Morson, Vol. 63, pp. 1-47. Springer-Verlag, Berlin-Heidelberg-New York (1976) Morson, B. c.: Gastric polyps composed of intestinal epithelium. Brit. J. Cancer 9, 550557 (1955) Nagayo, T.: Histological Diagnosis of Biopsied Gastric Mucosae with Special Reference to that of Borderline Lesions. In: Gann Monograph on Cancer Research, Ed. by T. Murakami, Vol II, pp. 245-256. University Park Press, Baltimore-LondonTokyo (1972) Nagayo, T., Ito, M., Yokoyama, H., and Komagoe, T.: Early phases of human gastric cancer: Morphological study. Gann 56, 101-120 (1965) Nagayo, T., and Yokoyama, H.: Recent changes in the morphology of gastric cancers in Japan. Int. ]. Cancer 21, 407-412 (1978) Rosch, W., and Koch, H.: Magenfriihkarzinom: Makroskopie und Biopsie. Erfahrungen bei 50 Fallen. Akr, Gastrologie 5, 239-246 (1976) Received October 10, 1978 . Accepted December 19, 1978

Key words: Early gastric cancer - Adenomatous polyps - Histology Differential diagnosis Aage Johansen, M.D., Dept. of Pathology, Bispebjerg Hospital, DK-2400 Copenhagen NV, Denmark