Journal of Surgical Oncology 5659-62 (1994)

H istogenesis of Small Colonic Adenocarcinomas

CARLOS RUBIO, MD, PhD, JAYANT SHETYE, MD, AND EDGAR JARAMILLO, MD

Departments of Pathology (C.R., I.S.) and Endoscopy (E.).), Karolinska Hospitaf, Stockholm, Sweden

It has been claimed that in order to identify the type of mucosal lesion which precedes colonic adenocarcinoma only those tumours measuring S 1 mm in diameter should be considered. The review of the English literature indicates that only 35 colorectal adenocarcinomas measuring S 1 cm in diameter have been so far reported. From the three cases of colonic adeno- carcinoma measuring 8 mm or less in diameter presented here, one adeno- carcinoma originated in a flat adenoma, the second in an exophytic tubular adenoma, and the third showed no adenomatous component. It would thus appear that colonic adenocarcinomas can originate not only from exo- phytic adenomas or from flat adenomas but also from apparently nonade- nomatous flat mucosa. 0 1994 Wiley-Liss, Inc.

KEY WORDS: colon cancer, microinvasive adenocarcinoma, flat adenomas

INTRODUCTION In an editorial introducing classic articles on colorectal

malignancies [l] it was stated that “before 1939 most physicians believed that cancers of the colon arose de novo, in otherwise normal bowel.” The work of Swinton and Warren [2] indicated, however, that colorectal carci- nomas often arose in pre-existing adenomatous polyps. The concept of “adenoma-carcinoma sequence” was later coined by Jackman and Mayo [3]. Years later, Castleman and Krickstein [4] claimed that “the majority of cancers of the colon arose as cancer ‘de novo’ or in villous ade- nomas.” Based on the study of 20 primary adenocarcino- mas measuring 2 cm or less in diameter, Spratt and Ack- erman [5] also reported that most colonic carcinomas arose from nonpolyploid lesions.

By the end of the fifties and early sixties, Morson [6] and Muto et al. [7] reviewed the concept of “adenoma- carcinoma sequence,” which has prevailed as the com- mon pathway of colorectal carcinogenesis. At this point it should be stressed that the adenomas referred to were exophytic lesions. More recently, Japanese authors [8 131 demonstrated that invasive adenocarcinomas in the colorectal mucosa could arise from flat adenomas.

The difficulties in studying the histogenesis of colorec- tal carcinomas are mainly related to the size of the mu- cosal lesions[ 141. In fact, large adenocarcinomas usually invade and eventually destroy initially noninvasive mu- cosal lesions. Consequently, only small mucosal lesions

0 1994 Wiley-Liss, Inc.

are suitable for the scrutiny of the histogenesis of colorec- tal adenocarcinomas .

In the present communication, we demonstrate that minute adenocarcinomas, i.e., up to 8 mm in diameter in the colon, may arise either from a flat adenoma, from an exophytic adenoma, or from atypical colonic mucosa without any adenomatous component.

CASE REPORTS Case 1

A 55-year-old male consulted for a 2-month-old dif- fuse left lower quadrant abdominal pain and obstipation. A colon enema revealed colonic diverticulosis and six polyps up to 1.5 cm in diameter in the left colon. At subsequent colonoscopy , eight exophytic polyps were detected and removed. The histological examination of all eight polyps demonstrated tubular or tubulovillous adenomas. One of the tubular adenomas (8 mm in diam- eter) had, in addition, a micro-adenocarcinoma invading the submucosal tissue (Fig. 1).

Case 2 A 64-year-old male complained of abdominal pain and

diarrhea. Two weeks before consultation he had noticed

Accepted for publication December 30, 1993 Address reprint requests to Carlos Rubio, Department of Pathology, Karolinska Hospital, S-104 01 Stockholm, Sweden.

60 Rubio et al.

Fig. 1. Adenocarcinoma invading the submucosal tissue, originating in an exophytic adenoma measuring 8 mm in diameter (H&E X80). Arrows: muscularis rnucosae.

blood streaks in his stools. At colonoscopy, seven ele- vated and one flat lesion, all of them measuring less than 1 cm in diameter, were observed and biopsied. The seven elevated lesions were hyperplastic (metaplastic) benign polyps. The flat lesion measured 5 mm in diameter and was completely removed at endoscopy. At histology, a flat adenoma with slightly packed tubuli was observed. The atypical nuclei in the tubuli reached the luminal aspect of the cylindrical cells (high-grade dysplasia) . Semi-serial sections demonstrated a micro-adenocarci- noma invading the upper part of the submucosal tissue (Fig. 2) . No atypical epithelium could be observed in any of the remaining biopsies.

Case 3 A 48-year-old male had been operated on two years

previously for an abscess in the left hip due to suppurative osteitis. One year later the patient donated bone marrow for transplantation to a brother. During the past 6 months, the patient complained of diffuse abdominal pain and periodic diarrhea, sometimes with blood streaks, as well as weight loss of 12 kg. Gastroscopic and rectoscopic

examinations were normal, but a colon enema showed a stricture in the sigmoid colon. At operation a tumour mass fixed to the urinary bladder was found as well as enlarged lymph nodes in the mesosigmoideum and in the lymph nodes along the abdominal aorta up to the kidney arteries. In addition, five metastatic nodules were pal- pated in the liver. The colon sigmoideum with the tumour was resected. The surgical specimen measured 20 cm in length. Six centimeters from the proximal section mar- gin, a 4-cm long, circular tumour was found growing into the pericolonic flat. Three isolated lymph nodes, up to 2 cm in diameter, were harvested. In addition, a minor, flat, slightly elevated, mucosal plaque measuring 5 mm in diameter was found. At histological examination, the large circular tumour was a moderately differentiated ad- enocarcinoma with transmural invasion. Two of the three regional lymph nodes had metastatic growth. The minor tumour of 5 mm in diameter was histologically a moder- ately differentiated adenocarcinoma invading the upper part of the submucosal tissue (Fig. 3). The limit between the adenocarcinoma and the adjacent normal mucosa was sharp. No exophytic or flat adenomatous lesion on the colonic mucosa covering, or adjacent to, the tumor was present. The postoperative course was uneventful. The patient is alive 6 months after the operation.

DISCUSSION There is much discussion regarding the histogenesis of

colonic adenocarcinoma. While many authors consider the adenoma-carcinoma sequence as an obligated path- way of colorectal carcinogenesis (without specifying whether the adenomas reviewed were exophytic or flat) [ 15,161, others [ 1 1,17-221 deny those possibilities and claim that adenocarcinomas in the colon arise de novo (i.e., without exophytic or flat associated intraepithelial lesions). The review of the illustrations in those publica- tions revealed, however, an intramucosal component in the shoulder of some of the lesions, suggesting remnants of a flat adenoma.

Another matter of concern is the definition of adeno- carcinoma. In the western world, adenocarcinomas of the colorectal mucosa are considered those lesions invading the submucosal compartment (except in those rare cases with signet ring cell adenocarcinoma showing invasion of the lamina propria mucosae exclusively). On the other hand, some Japanese pathologists regard as adenocarci- nomas even tubular lesions confined to the mucosal layer only, which are referred to as “intramucosal carcino- mas.” Western pathologists, however, regard those le- sions as adenomas with high-grade dysplasia without in- vasion. In the past, many of those lesions were diagnosed in the west as “carcinomas in situ” but the term was abandoned because of overtreatment in many cases [6,151.

Histogenesis of Small Colonic Adenocarcinoma 61

Fig. 2. in diameter (H&E X40. Arrows: muscularis mucosae.

Adenocarcinoma invading the submucosal tissue, originating in a flat adenoma measuring 5 mm

In a recent publication [23], eight leading gastrointesti- nal Japanese pathologists reviewed 33 colorectal neopla- sias: agreement in diagnosis as to whether the lesions were adenomas, borderline lesions, or adenocarcinomas was reached in only 18% (or in 6 of 33) of the cases. This recent study indicates the difficulty in diagnosing adeno- carcinomas when the criteria used do not include the invasion of the submucosal layer.

In the literature, only 142 adenocarcinomas measuring S 3 cm in diameter have been reported (Table I). Of these, only 35 were not larger than 1 cm in diameter. Some authors believe that lesions measuring 3 cm in diameter are already too large to assess the nature of the initial intramucosal lesion and claim that only those mea- suring 1.5 cm [23] or S1 cm [9,16] qualify for this type of investigation.

Of the three adenocarcinomas reported here, measur- ing not beyond 8 mm in diameter, one arose in an exo- phytic tubular adenoma, the second in a flat adenoma, and the third was apparently a de novo adenocarcinoma (i.e., without any adenomatous-associated lesion). It should be pointed out that the luminal aspect of the latter adenocarcinoma was composed of densely packed tu- bules with highly atypical cells (Fig. 3). The possibility that the invasive carcinoma had originated in a minute flat adenoma, limited strictly to the mucosa covering the in- vading area, cannot be disregarded.

In conclusion, the results presented above indicate that

Fig. 3. Adenocarcinoma invading the submucosal tissue, arising de novo. The lesion measured 5 mm in diameter (H&E X 130). Arrows:

adenocarcinomas in the colonic mucosa may arise either in exophytic adenomas, in flat adenomas Or possibly de novo. Further studies are necessary to assess the fre- muscularis mucosae. Inset: overview of the same tumour.

62 Rubio et al.

TABLE I. Number of Colorectal Adenocarcinomas Reported in the Literature Measuring 3 cm or Less in Largest Diameter

Adenocarcinomas (size)

Year <3 cm <2 cm <1.5 cm <1 cm All Author

Helwig [14] 1947 Spratt and Ackerman [5] 1962 Spjut et al. [22] 1979 Crawford and Stromeyer [Zl] 1983 Jelinek et al. [17] 1983 Adachi et al. [8] 1988 Kuramoto and Oohara [12] 1989 Karita et al. [lo] 1991 Bedenne et al. [18] 1992 Iishi et al. [9] 1992 Present series 1993 Total

2 10 3 7

4 2 1

1 3 7 15

20 59

5 3

20 73 14 35

2 20 4 2 1 I

25 20 59

5

142

quency of minute colonic adenocarcinomas arising in each one of the above-mentioned lesions.

ACKNOWLEDGMENTS This study was supported by grants from the Cancer

Fund and the Cancer Society, Stockholm, Sweden.

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