In tra - €pit helial Esophageal

HlROYUKl KUWANO, MD, HlROYUKl

Carcinoma Concomitant With Squamous Cefl Carcinoma

MATSUDA, MD, HIDE0 MATSUOKA, MD, HIDENOBU KAI, MD, YASUYUKI OKUDAIRA, MD, AND KEIZO SUGIMACHI, MD, FACS

A review of 222 cases of squamous cell carcinoma of the esophagus revealed 67 (30.2%) with intra- epithelial carcinoma, contiguous with the main lesion. The incidences of such lesions were 10.9% and 68.0% in those given and not given preoperative irradiation, respectively. The 222 tumors were grouped into five categories, according to depth of invasion of the main lesion, those restricted to the mucosa, submucosa, proper muscular layer, and those invading the adventitia and neighboring structures. The rates of occurrence of intra-epithelial carcinoma were 87.5,65.0, 26.9, 18.8, and 17.7%, respectively. Of the 67 with intra-epithelia! carcinoma, the incidences of both proximal and distal location of such lesions were 85.7% in mucosal carcinoma, 84.6% in submucosal carcinoma, 71.4% in cancer restricted to the proper muscular layer, 50.0% in cancer invading the adventitia, and 9.1% in cancer invading the neighboring structures. Intra-epithelial carcinoma may thus originate from field carcinomatous transformation rather than from an intra-epithelial spread of the main lesions. These observations also support the concept of the field origin of carcinogenesis in the esophagus.

Cancer 59:783-787, 1987.

HE OCCURRENCE OF INTRA-EPITHELIAL CARCINOMA T of the esophagus associated with invasive carcinoma has important implications both for the evaluation of the extent of surgical treatment and for understanding the pathogenesis of esophageal carcinoma. Despite the clinical and pathological significance of intra-epithelial carcinoma concomitant with esophageal carcinoma, few detailed histopathologic studies concerning its incidence, extent, and relationship with the main carcinoma, have been documented?-’

The histogenesis of intra-epithelial carcinoma of the esophagus concomitant with invasive squamous cell car- cinoma of the esophagus has not been clearly established. It has generally been interpreted to be the result of an intra-epithelial spread of the invasive carcinoma.”

We reported the high incidence of glandular or mucus- secreting areas in esophageal cancer, evidence which seems to support the concept of the field carcinogenesis of esophageal ~arcin0ma.l~ In the current study, we histo- pathologically analyzed lesions of squamous cell carci- noma containing the area of intra-epithelial carcinoma,

From the Department of Surgery 11, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Address for reprints: Hiroyuki Kuwano, MD, Department of Surgery 11, Faculty of Medicine, Kyushu University 60, 3-1-1, Maidashi, Higashi- ku, Fukuoka 812, Japan.

The authors thank M. Ohara for critical reading of the manuscript. Accepted for publication September 10, 1986.

with special attention directed to the mode of origin of esophageal cancer.

Materials and Methods

Three hundred individuals with primary esophageal carcinoma underwent esophageal resection in the De- partment of Surgery 11, Kyushu University from 1965 to 1985. Excluding the 78 with tumors that were completely destroyed by preoperative irradiation or were cases of ad- enocarcinoma, 222 cases were reviewed in the current study. Of these 222, preoperative irradiation was given to 147 patients. Preoperative irradiation was performed with ‘OCo or linear accelerator units at a daily dose of 200 rad (overall dose, 3000 to 4000 rad within 1 month). Micro- scopic sections of the whole resected esophagus were made from step-sectioned blocks 0.5 cm in width and stained with hematoxylin and eosin (H & E).

To diagnose intra-epithelial carcinoma, we followed the criteria of Suckow et ~ 1 . : ~ (1) absence of cellular differ- entiation with variations in size and shape and hyper- chromatism of the nuclei with increased mitotic activity; (2) the aforementioned changes must involve the entire thickness of the epithelium and may involve submucous glands and ducts; and (3) intact basement membrane. Ex- cluding cases of multiple intra-epithelial carcinoma, car- cinomatous lesions associated with intra-epithelial por- tions of continuous malignant changes were analyzed.

The incidence and location of intra-epithelial carci-

783

784 CANCER February 15 1987 Vol. 59

c

._ r

FIG. I . Portion of intra-epithelial carcinoma of the esophagus with lymphoid reaction, beneath the basal layer of the epithelium (H & E, X124).

noma were analyzed in five groups, prepared according to the depth of invasion of the main lesion, those restricted to the mucosa, submucosa, proper muscular layer, and invasion into the adventitia and neighboring structures. Average age and sex of the patients, location of the lesion, representative histologic type, occurrence of lymph node metastasis, and survival rate were also evaluated in both groups, with and without intra-epithelial carcinoma. Sur- vival rates were estimated on the basis of the Kaplan and Meier method14 and probability values for comparing two sets of life table data were determined using the generalized Wilcoxon test.15 Cases of death due to operative compli- cations and causes other than the tumor were excluded from analysis.

Results

Among 222 Japanese patients with squamous cell car- cinoma of the esophagus, there were 67 (30.2%) with an intra-epithelial carcinoma.

Typical histologic features of the intra-epithelial car- cinoma are shown in Figure 1. In some cases, ducts of esophageal glands were also involved (Fig. 2).

Clinicopathologic details of those with and without in- tra-epithelial carcinoma are given in Table 1. There were no significant differences in the clinicopathlogic charac-

teristics among the groups, except for the incidence of preoperatively irradiated cases.

The average length of the lesions with and without intra- epithelial carcinoma was 4.7 k 3.4 cm and 4.4 k 2.3 cm, respectively. The incidences of coexistence of epithelial dysplasia were 16.4% in cancer with intra-epithelial car- cinoma and 1 1 .O% in cancer without it, and the incidences of positive cancer tissue at the proximal stump of resected esophagus were 6.0% and 1.9% in cancer with and without intra-epithelial carcinoma, respectively. However, there were no statistical differences in these three factors be- tween both groups.

Of the 67 patients with intra-epithelial carcinoma, pre- operative irradiation therapy was given to 16 and the in- cidences of intra-epithelial carcinoma concomitant with squamous cell carcinoma of the esophagus, with and without preoperative irradiation, were 10.9% and 68.0%, respectively.

The incidences of the occurrence of intra-epithelial carcinoma in each group, divided according to the depth of invasion of the main lesion such as that restricted to the mucosa, submucosa, proper muscular layer, that in- vading the adventitia and neighboring structures, were 87.5, 65.0, 26.9, 18.8 and 17.7%, respectively. The more advanced the lesion, the lower the incidence of intra-ep- ithelial cancer (Table 2). The location of intra-epithelial

No. 4 INTRA-EPITHELIAL ESOPHAGEAL C A K U W U n O el Ul. 785

FIG. 2. Intra-epithelial carcinomatous change involving the duct of the esophageal gland (H & E, X93).

carcinoma with regard to the main lesion was also eval- uated. The incidences of both proximal and distal local- ization of intra-epithelial carcinoma among those with

TABLE 1. Clinicopathologic Features of Squamous Cell Carcinomas With and Without Intra-Epithelial Carcinoma

Intra-Epithelial Carcinoma

Positive Negative (67 cases) ( 155 cases)

Average age (yr) 61.7 63.7 Sex (male/female) 6.4: 1 5.0: 1 Location

Upper 7 (10.5)* 16 (10.3) Middle 41 (61.2) 99 (63.9) Lower 19 (28.4) 40 (25.8)

Not given 51 (76.1) 24 (15.5) Given 16 (23.9) 131 (84.5)

Preoperative irradiation

Differentiation of squamous cell carcinoma of main lesion

Well 14 (20.9) 35 (22.6) Moderately 44 (65.7) gO(51.6) Poorly 7 (10.4) 39 (25.2) Undifferentiated 2 (3.0) 1 (0.6)

(+I 31 (45.5) 87 (56.1) (-1 36 (54.5) 68 (43.9)

* Numbers in parentheses = %.

Lymph node metastasis

such lesions were 85.7, 84.6, 7 1.4, 50.0, and 9.1 % in mu- cosal, submucosal carcinoma, that restricted to the proper muscular layer, that invading the adventitia, and neigh- boring structures, respectively, thereby revealing a higher rate in the earlier cancer (Table 3).

Of 188 patients with esophageal squamous cell carci- noma, 57 with intra-epithelial carcinoma and 13 1 without it were analyzed in terms of the postoperative prognosis, excluding 34 who died of operative complications and causes other than the tumor. Figure 3A shows the survival curves of 188 patients. The survival rate at the postop- erative 36th month was 47.6 and 16.2%, in those with and without areas of intra-epithelial carcinoma, respec- tively. The difference in survival rate between the curves was statistically significant ( P < 0.00 1) . However, because the distribution of the depth of invasion of the main le-

TABLE 2. Incidence of Intra-Epithelial Carcinoma

Depth of invasion of main lesion Incidence (%)

Restricted to within the mucosa 718 (87.5) Restricted to the submucosa 26/40 (65.0) Proper muscular layer 7/26 (26.9) Invading the adventitia 16/85 (18.8) Invading the neighboring structures 11/62 (17.7)

Total 671222 (30.2)

786 CANCER February 15 1987 VOl. 59

1

TABLE 3. Location of Intra-Epithelial Carcinoma With Regard to the Main Lesion

Depth of invasion of Proximal main lesion and distal Proximal Distal Side

Restricted to within the mucosa (7) 6 (85.7)* l(14.3) 0 0

Restricted to the submucosa (26) 22 (84.6) 3 (11.5) l(3.8) 0

Proper muscular layer (7) 5 (71.4) 0 l(14.3) l(14.3)

Invading the adventitia (16) 8 (50.0) 0 7 (43.8) 1 (6.3)

Invading the neighboring structures ( 1 1) 1 (9.1) 7 (63.6) 2 (18.2) 1 (9.1)

Total (67 cases) 42 (62.7) 11 (16.4) 11 (16.4) 3 (4.5)

* Number in parentheses = %.

sions differed in those with and without intra-epithelial carcinoma, the survival rates of both groups were com- pared in cases of depth of invasion of the main lesion. The survival rates of those with and without intra-epithe- lial carcinoma at the postoperative 36th month were 75.5 and 50.3% in cases when the lesion was restricted to the

I I I

0' 6 12 18 24 30 36 A months after operation ( m

intra-epithelial ca. (+) (N=7) -

_ _ _ .- 2 t L 7

2 50- L7

1 I I I I 1 0 6 12 18 24 30 36 C months after operation ( m

mucosa or submucosa (Fig. 3B), 53.6 and 16.7% in those with invasion into the proper muscular layer (Fig. 3C), 1 1.1, and 15.6% in those with invasion into the adventitia or neighboring structures (Fig. 3D). Although there were no statistical significances between esophageal cancer with and without intra-epithelial carcinoma in each group, those with intra-epithelial carcinoma seemed to have a more favorable prognosis, at least in cases of earlier car- cinomas.

Discussion

Intra-epithelial carcinoma contiguous with squamous cell carcinoma of the esophagus has been considered rare. In 1962, Suckow et al.' reported six cases of esophageal carcinoma associated with extensive intra-epithelial car- cinomatous changes in which the entire specimen was studied using a step-sectioned technique. Soga et al l2 found that, among 179 cases, 1 1 (6.1%) had the superficial spreading type of esophageal carcinoma, defined as lesions with an intramucosal extension of carcinoma 20 mm or more from the main lesion. Mandard et a1." studied 39 specimens of invasive esophageal squamous cell carci- noma and demonstrated that in situ carcinoma contiguous to the invasive cancer was present in 18 of 26 patients not given preoperative irradiation (69.2%) and in 2 of 13 given radiation therapy preoperatively (1 5.3%). Our study

I

intraepithelial ca. (-1 ( N=13 1

I I

6 12 18 24 30 36 months after operation (m) B o

loor-

intra-epithelial ca. (+) L-l

-1

FIGS. 3A-3D. Survival of all patients with esophageal squamous cell carcinoma, with and without intra-epithelial carcinoma. (A) There is a statistical significance (P i 0.001) (B, C, D). Survival of those with tumors restricted to the submucosal layer, proper muscular layer, those invading adventitia, or neighboring structures, respectively.

No. 4 INTRA-EPITHELIAL ESOPHAGEAL CA - Kuwano et al. 787

revealed that, in serial investigations of all ranges of the resected esophagus, 30.2% of the esophageal squamous cell carcinoma contained an area of intra-epithelial car- cinoma, contiguous to the main lesion, and the incidences with and without preoperative irradiation were 10.9% and 68.0% respectively. These findings are similar to those of Mandard et al."

Areas o f intra-epithelial carcinoma concomitant with esophageal carcinoma have usually been considered a lat- eral intra-epithelial spread from the main tumor. The theory of a multiple or widespread carcinomatous trans- formation of the mucosa in the occurrence of such lesion has not gained much support. O'Gara and Horn' and Suckow et al.9 reported cases of esophageal carcinoma with widespread mucosal involvement in which almost all of the entire esophageal mucosa revealed intra-epithe- lial carcinoma. They suggested the possibility of field car- cinomatous transformation. In the current study, we an- alyzed the incidence and the location of intra-epithelial carcinoma in each group, divided according to the depth of invasion of the main lesion. It was evident that the greater the invasion of the main lesion, the lower were the incidences of intra-epithelial carcinoma and both proximal and distal locations. If it is assumed that the depth of invasion of the main lesion expresses the duration after carcinogenesis, and if intra-epithelial carcinoma were the result of a lateral intra-epithelial spread from the main lesion, the incidence of such a lesion and its bilateral lo- cation should be higher in advanced than in earlier cases. However, our study revealed that the incidence was higher in earlier cases, thereby suggesting a field carcinomatous transformation as the main origin of such lesions. Willis advocated the concept of field origin of the tumor in his work Pathology of Tumours, but no solid basis of support was given.I6 Recently, we reported the high incidence of glandular or mucus-secreting areas in esophageal squa- mous cell carcinoma (2 1 .OW) and the cases of early esoph- ageal carcinomas simultaneously included two histolog- ically different components, in situ squamous cell carci- noma and glandular carcinoma, thereby supporting the concept of field carcinogenesis of esophageal carcinomas. l 3

The significance of this type of lesion for prognosis is not well understood. Despite the lack of statistical differ- ences, there was a tendency for patients with intra-epi- thelial carcinoma to have a favorable prognosis in cases of earlier cancer, compared to findings in those without such lesions. We analyzed the various prognostic factors and the multifactorial analyses showed that the so-called intra-epithelial carcinomatous spread was one factor in- dicative of a favorable prognosis."

Our current study also demonstrated that there is a considerable difference in the occurrence of intra-epithelial

carcinoma between those patients given and not given preoperative irradiation. It remains to be determined if the preoperative irradiation cured such lesions or accel- erated the subepithelial invasion.

The theory of widespread epithelial carcinomatous transformation seems to be the most acceptable expla- nation of the histogenesis of the intra-epithelial carcino- matous area. Our current clinical approaches are based on the theory of a field carcinogenesis of squamous cell carcinoma of the esophagus.

Concerning the significance of preoperative irradiation therapy, such treatment does reduce the occurrence of intra-epithelial carcinomatous areas. However, in this study, we excluded cases of esophageal cancer that were completely destroyed by preoperative irradiation, there- fore, speculation on the merits or dements of this therapy is not valid at this point.

REFERENCES

1. Imbriglia JE, Lopusniak MS. Cytologic examination of sediment from the esophagus in a case of intra-epidermal carcinoma of the esoph- agus. Gastroenterology 1949; 13:457-463.

2. OGara RW, Horn RC. Intramucosal carcinoma ofthe esophagus: Report of a case. Arch Pathol 1955; 60:95-98.

3. Suckow EE, Staley CJ, Brock DR. Extensive intra-epithelial car- cinoma of the esophagus with multiple invasive sites. Bull Northwestern Univ Med School 1961; 35:45-47.

4. Ushigome S, Spjut HJ, Noon GP. Extensive dysplasia and carci- noma in situ of esophageal epithelium. Cancer 1967; 20:1023-1029.

5. Steifert E, Borst HH, Ostertag H ef a/. Carcinoma in situ of the esophagus (early esophageal cancer): A case report and a review of the literature. Endoscopy 1973; 5: 147-153.

6. Bishop D, Lushpian A, Louis C. The cytology of carcinoma in situ and early invasive carcinoma of the esophagus. Acta Cytol 1977; 21:

7. Bergman F. Cancer of the esophagus: A histological study of de- velopment and local spread of 10 cases of squamous cell carcinoma in the lower third of oesophagus. Acta Chir Scand 1959; 117:356-365.

8. Steiner PE. The etiology and histogenesis of carcinoma of the esophagus. Cancer 1956; 9:436-452.

9. Suckow EE, Yokoo H, Brock DR. Intraepithelial carcinoma con- comitant with esophageal carcinoma. Cancer 1962; 15:733-740.

10. Mandard AM, Tourneux J, Gignoux M, Blanc L, Segol P, Man- dard JC. In situ carcinoma of the esophagus: Macroscopic study with particular reference to the Lugol test. Endoscopy 1980 12:5 1-57.

1 1. Barge J, Molas G, Maillard JN, Fekete F, Bogomoletz WV, Potet F. Superficial oesophageal carcinoma: An oesophageal counterpart of early gastric cancer. Histopathology I98 1; 5:499-5 10.

12. Soga J, Tanaka 0, Sasaki K, Kawaguchi M, Muto T. Superficial spreading carcinoma of the esophagus. Cancer 1982; 50: 164 1-1645.

13. Kuwano H, Ueo H, Sugimachi K, Inokuchi K, Toyoshima S, Enjoji M. Glandular or mucus-secreting components in squamous cell carcinoma of the esophagus. Cancer 1985; 56514-518.

14. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-481.

15. Gehan EA. A generalized Wilcoxon test for comparing arbitrarily singly censored samples. Biometrika 1965; 52:203-223.

16. Willis RA. Mode of origin of tumours. In: Pathology of Tumours, ed. 4. London: Buttenvorths, 1967; 105-124.

17. Matsuura H, Sugimachi K, Kuwano H, Koga Y, Okamura T. Malignant potentiality of squamous cell carcinoma of the esophagus predictable by DNA analysis. Cancer 1986; 57: 18 10-1 8 14.

298-300.