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Squamous epithelial dysplasia associated with squamous cell carcinoma of the esophagus
Cancer Letters. 72 (1993) 141-147 Elsevier Scientific Publishers Ireland
Squamous carcinoma
141 Ltd.
epithelial dysplasia of the esophagus
Hiroyuki Kuwano, Masayuki Watanabe, Masaki Mori and Keizo Sugimachi
associated
Noriaki
with squamous
Sadanaga,
Masahiko
cell
Ikebe,
Department of Surgery II, Facult_v of Medicine, Kyushu University, Fukuoka (Japan) (Received (Revision (Accepted
26 March 1993) received 18 May 1993) 19 May 1993)
Summary To investigate the relationship between dysplasia and carcinoma of the esophagus, 159 cases of esophageal carcinoma without any preoperative treatment were reviewed retrospectively. There were 75 dysplastic lesions in 32 cases (20.1%). The incidence of co-existence of dysplastic lesions was 0, 58.3, 31.3, 20.8 and 11.4% in intra-epithelial, mucosal and submucosal cancers and those invading the proper muscular layer and advantitia, respectively. Thus, excluding the cases of intraepithelial carcinoma, the less advanced the lesion, the higher the incidence of dysplasia. Epithelial dysplastic lesions were classified as 12 with mild, 33 with moderate and 30 with severe degrees of dysplasia. Although the continuity of dysplastic lesions to the areas of carcinoma was not so frequent (48.0%). it was more often encountered in severe dysplasia rather than in moderate or mild dysplasia, which suggested some relationship between the severity of dysplasia and carcinoma. In the cases with a dysplastic lesion the multiplicity of squamous cell carcinoma and the intra-epithelial spread of the main lesion were more frequently seen (P < O.OOl), suggesting a multicentric occurrence of dysplastic lesions and carcinomas. Correspondence 10: Hiroyuki Kuwano. Department of Surgery II, Faculty of Medicine, Kyushu University, 3-l-l Maidashi, Higashi-ku, Fukuoka 8 12, Japan.
Keywords: esophageal cancer; squamous cell carcinoma; dysplasia; carcinogenesis; multiple cancer Introduction Squamous epithelial dysplasia is frequently encountered in the esophagus with squamous cell carcinoma [9], and several studies have suggested its significance as a precancerous lesion [1,10,11,13]. Takubo et al. [16] found epithelial dysplasia of the esophageal mucosa and subclinical carcinoma in 67 (27%) and 6 (2.4%) out of 25 1 autopsied cases of non-esophageal carcinoma, respectively, and suggested that epithelial dysplasia could thus be the site of origin for cancer development. Mukada et al. [lo] revealed the progression of esophageal epithelial dysplasia towards in situ carcinoma as studied by cytofluorometric methods, using estimated Feulgen-DNA values for the histopathological grading of esophageal dysplasia. However, it has yet to be elucidated whether epithelial dysplasia in the esophagus is a pre-cancerous lesion or a co-existing lesion with esophageal cancer. In addition, the significance of the dysplasia as a histogenesis of the esophageal squamous cell carcinoma has also not yet been clearly demonstrated. Recently we performed a serial histological investigation of squamous epithelial dysplasia associated with carcinoma of the esophagus and demonstrated that many dysplastic lesions were
142
located separately from the carcinoma, and demonstrated a negative dysplasia-carcinoma sequence in many esophageal cancers [ 121. Moreover, we also collected minute foci ( < 10 mm in diameter} from the specimens of the excised esophagus and demonstrated that there was no continuity between the minute foci of carcinoma and dysplasia 131. Thus the histogenes~s of esophageal cancer is still controversial, and previous studies on lesions at an advanced stage have not been informative. In the current study we performed a serial histopathological investigation of esophageal squamous cell carcinoma, on the basis of continuity and co-existence with several degrees of epithelial dysplasia, while also directing o;lr attention to the histopathological signi~cance of epithelial dysplasia.
Materials and Methods Five hundred and fifty-two patients with primary esophageal carcinoma underwent esophageal resection in the Second Department of Surgery, Kyushu University, Fukuoka, Japan, from January 1965 to May 1991. Among these cases, excluding 393 patients with adenocarcinoma and those with gre-operative treatments, such as irradiation [ 1.41,hyperthermo-chemo-radiotherapy [ 1S] or neo-adjuvant chemotherapy, we reviewed 159 who had undergone no pre-operative treatment. Microscopic sections of the whole resected esophagus were prepared from step-sectioned blocks 5 mm wide and were stained with hematoxylin and eosin. For the histological diagnosis of squamous epithelial dysplasia we used the criteria defined by
Fig. 1. Mild dysplasia. The basal ceils in the bottom third ofthe epithelium are hyperchromatic. vary in size and demonstratemitotic activity above the level of the basement membrane (H&E. 410x ).
143
the World Health Organization’s International Histological Classification of Tumours in 1990 1171,according to which the nuclei of the lesion are enlarged and hyperchromatic while showing increased mitotic activity. In the case of mild dysplasia, such atypical nuclei are limited to the basal zone, and there is evidence of cytoplasmic maturation superficially (Fig. 1). With increasing grades of dysplasia there is a progressive increase in the proportion of atypical basal cells, until the entire thickness of the epithelium is replaced. Therefore moderate dysplasia was diagnosed when an intra-epithelial lesion similar to mild dysplasia with an atypical proliferative zone expanding up to one-half the thickness of the epithelium was found (Fig, 2). Severe dysplasia was defined as an intra~pithelial lesion with an atypical proliferative
Fig. 2.
440X).
zone encompassing up to three-quarters of the epithelium (Fig. 3). In addition, a diagnosis of intra-epithelial carcinoma was made when an epithelium was either completely or almost completely composed of atypical immature cells but lacking in invasive growth (Fig. 4). The number of various lesions were counted by a histological diagram while mapping their extent in two dimensions, and these lesions were then investigated with regard to the presence or absence of continuity to the areas of carcinoma. Clinicopathological factors were compared between the cases with and without areas of squamous epithelial dysplasia, and a chi-squared test was used for the statistical analysis.
Moderate dysplasia. An atypicat proliferative zone expanding up to one-half the :hickness of the epithelium is found (H&E.
Fig. 3.
Severe dysplasia.
An atypical
zone encompassing
up to three-quarters
Results A serial histological review of 159 specimens from patients with squamous cell carcinoma revealed 75 dysplastic lesions in 32 cases (20.1%). In three cases of intra-epithelial carcinoma (which is non-invasive carcinoma) there was no lesion of dysplasia, while 7 out of 12 cases (58.3%) with mucosal cancer (which invaded but were restricted to within the proper mucosal layer), 10 out of 32 (31.3%) with submucosal carcinoma, 5 out of 24 (20.8%) with carcinoma invading the proper muscular layer and 10 out of 88 tumors (11.4%) invaded as far as the adventitia contained areas of dysplasia in the esophagus. Thus, excluding the cases of intra-epithelial carcinoma, the less the cancer invaded, the higher the frequency of coexistence of dysplasia. There were 17 lesions of dysplasia consisting of 5 mild, 7 moderate and 5
of the epithelium
(H&E. 410
x )
with severe degrees of dysplasia in mucosal cancer, 1 mild, 10 moderate and 12 with severe dysplastic areas among 23 dysplastic lesions in submucosal cancer and 3, 8 and 17 and 3, 8 and 6 of mild to severe dysplasia in cancer invading the proper muscular layer and adventitia, respectively. Thus there were a total of 12, 33 and 30 lesions of mild, moderate and severe dysplasia, respectively (Table I). The relationship between the grade of dysplasia and the continuity to areas of carcinoma is shown in Table II. Although the frequency of continuity of the dysplasia to the carcinoma was not high (48.0%), the more severe the grade of dysplasia, the higher the frequency of continuity to the areas of carcinoma. The clinicopathological features of esophageal cancer, both with and without dysplasia, were also analyzed. There was no difference between the groups regarding age, sex distribution, location or
Fig. 4. Intra-epithelial brane (H&E, 410 x ).
carcinoma.
Co-existence
of various
Table 1.
Depth of invasion lesion
The entire thickness
degrees
of the main
of squamous
Submucosal
[31 [I21
Proper
muscular
Adventitia
Total
[321
layer
layer
epithelial
is composed
dysplasia
of atypical
cells, with an intact basement
and carcinoma.
Dysplasia Cases
Epithelium Mucosal layer
of the epithelium
~241
Lg81
[I591
0 (0) 7 (58.3)
10 (31.3)
5 (20.8)
IO (11.4)
32 (20.1)
Number
Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe
of lesions
(‘X)
5 7 5
17
IO
23
12 3 8
18
3 8 6
17
12 33 30
75
146
Table II. Continuity of dysplasia. Degrees of dysplasia (lesions)
between carcinoma
degrees
Table III. Clinicopathological with and without dysplasia.
features
of esophageal
cancer
Dysplasia
Continuity (+)
WI
and various
(-) %
Mild Moderate Severe
I331 I301
3 (25.0) 15 (45.5) 18 (60.0)
9 (75.0) 18 (54.5) 12 (40.0)
Total
[751
36 (48.0)
39 (52.0)
depth of the invasion of the main lesion, the frequencies of lymph node metastasis, the intraepithelial spread of the main lesion of esophageal cancer, lymphatic vessel permeation or vascular permeation of the carcinoma. However, the incidence of multiplicity of squamous cell carcinoma within the esophagus and the intra-epithelial spread of the main lesion was significantly higher in the group with dysplasia than in that without it (P < 0.001) (Table III).
Age Sex (M/F) Location
(+)
II= 127
n = 32
63.1 zt 9.7 107120
62.7 f 12.4 2814 % 4 (12.5) 19 (59.4) 9 (28.1)
17 (13.4) 65 (51.2) 45 (35.4)
Upper Middle Lower
Depth of invasion of the main lesion 3 (2.4) Epithelium 5 (3.9) Mucosa 22 (17.3) Submucosa 9 (15.0) Proper muscular 78 (61.4) Adventitia Lymph
Multiplicity (-) (+)
(21.9) (31.3) (15.6) (31.3)
57 (44.9) 70 (55.1)
23 (71.9) 9 (28.1)
of squamous cell carcinomab 119 (93.7) 8 (6.3)
23 (71.9) 9 (28.1)
spread
(-) (+) Lymphatic
of the main lesionbJ 73 (58.9) 4 (12.5) 51 (41.1) 28 (87.5)
vessel permeation’
(-) (+) Vascular
0 7 10 5 10
node metastasis”
(-) (+)
Intra-epithelial
To investigate the histogenesis of esophageal cancer, we demonstrated the high incidence of either glandular or mucus-secreting components in esophageal squamous cell carcinoma [4], the frequent co-existence of intra-epithelial carcinoma contiguous to the main squamous cell carcinoma in early esophageal cancer [5], the close relationship between multiplicity and the existence of intra-epithelial carcinoma with squamous cell carcinoma [6] and the high incidence of co-existence of intra-epithelial carcinoma and glandular differentiation, particularly in early cancers [7]. These results were thus thought to support the possibility of the concept of either multicentric or field carcinogenesis in esophageal cancer. To investigate the pathological significance of dysplasia as a pre-cancerous lesion, a careful chronological observation of the lesion is essential. it is quite difficult to investigate However, chronological change using biopsy specimens of human materials. Therefore the serial histopatho-
(-)
56 (45.2) 68 (54.8)
22 (68.8) 10 (31.3)
88 (71.0) 36 (39.0)
22 (68.8) 10 (31.3)
permeationC
(-) (+) “P < 0.01.
bP < 0.001. CExcluding the three with intra-epithelial
carcinoma.
logical observation of the relationship between carcinoma and dysplasia in the resected esophagus would be useful, and from this viewpont the continuity of both lesions could also be important. From the current study, as well as our recent investigations of esophageal dysplasia [3,8,12], it was demonstrated that the continuity of dysplastic lesions to the areas of carcinoma was more often
147
encountered in severe dysplasia than in moderate or mild dysplasia, although it was not frequent. We also performed a cytophatometric DNA analysis of chemically induced esophageal carcinoma in rats, and demonstrated that the biological nature of severe dysplasia might thus be considered as serious a lesion as cancer itself [2]. Although dysplasia to the carcinoma sequence could not be denied, the possibility is that severe dysplasia contiguous to the carcinoma would already have a malignant biological nature and that various degrees of dysplasia would probably occur in an esophagus containing carcinoma. The current study also demonstrated that the multiplicity of squamous cell carcinoma and the intra-epithelial spread of the main lesion of carcinoma were more frequently seen in the cases with dysplasia than in those without it. If it is assumed that an intra-epithelial lesion contiguous to the invasive cancer originates as a field effect, the various degrees of lesions such as dysplasia and carcinoma may thus occur either multicentrically or with field effects in the same esophagus and especially in those containing dysplastic lesions.
5
6
7
8
9
10
11
12
References Crepsi. M., Munoz, N., Grassi, A., Quiong, S., Jing, W.K. and Jien, L.J. (1984) Precursor lesions of oesophageal cancer in a low-risk population in China: comparison with high risk populations. Int. J. Cancer, 34, 599-602. Koga, Y., Sugimachi, K., Kuwano, H.. Mori, M. and Matsufuji, H. (1988) Cytophotometric DNA analysis of esophageal dysplasia and carcinoma induced in rats by Nmethyl-N-amylnitrosamine. Eur. J. Cancer. Clin. Oncol., 24, 643-651. Kuwano, H., Morita, M., Matsuda, H., Mori, M. and Sugimachi, K. (1991) Histopathologic findings of minute foci of squamous cell carcinoma in the human esophagus. Cancer, 68, 2617-2620. Kuwano, H., Ueo. H., Sugimachi. K.. Inokuchi. K., Toyoshima, S. and Enjoji, M. (1985) Glandular or mucus secreting components in squamous cell carcinoma of the esophagus. Cancer. 56, 5 14-5 18.
13
14
15
16
17
Kuwano, H., Matsuda, H., Matsuoka. H., Kai. H., Okudaira, Y. and Sugimachi, K. (1987) Intra-epithelial carcinoma concomitant with esophageal squamous cell carcinoma. Cancer, 59, 783-787. Kuwano, H., Ohno, S., Matsuda, H., Mori. M. and Sugimachi, K. (1988) Serial histologic evaluation of multiple primary squamous cell carcinoma of the esophagus. Cancer. 61. 1635-1638. Kuwano, H., Nagamatsu, M., Ohno, S., Matsuda, H., Mori, M. and Sugimachi, K. (1988) Coexistence of intraepithelial carcinoma and glandular differentiation in esophageal squamous cell carcinoma. Cancer, 62, 1568-1572. Kuwano, H., Baba, K., Ikebe, M., Adachi, Y., Toh, Y. and Sugimachi, K. (1993) Histopathology of early esophageal carcinoma and squamous erithelial dysplasia. Hepato-gastro Enterol.(in press). Mandard, A.M., Marnay, J., Gignoux. M., Segol, P.. Blanc, L., Olliver, J.M., Bore], B. and Mandard. J.C. (1984) Cancer of the esophagus and associated lesions: detailed pathologic study of 100 esophagectomy specimens, Hum. Pathol., 15, 600-669. Mukada, T., Sasano, N.. Sato and E. (1978) Evaluation of esophageal dysplasia by cytafluoromeric analysis. Cancer. 41, 1399-1404. Munoz, N., Crepsi, M., Grassi, A.. Qning, W.G.. Quing, S.. Cai. L.Z. (1982) Precursor lesions of oesophageal cancer in high-risk populations in Iran and China. Lancet, 17 (i), 876-879. Nagamatsu, M., Mori, M., Kuwano, H., Sugimachi, K. and Akiyoshi, T. (in press) Serial histologic investigation of squamous epithelial dysplasia associated with carcinoma of the esophagus. Cancer. Qui, S. and Yang, G. (1988) Precursor lesions of esophageal cancer in high-risk populations in Henan Province, China. Cancer, 62, 551-557. Sugimachi, K., Matsufuji, H.. Kai, H., Matsuda. H., Ueo, H. and Inokuchi, K. (1986) Preoperative irradiation for carcinoma of the esophagus. Surg. Gynecol. Obstet., 162, 544-546. Sugimachi, K. and Inokuchi, K. (1986) Hyperthermochemoradiotherapy and esophageal carcinoma. Semin. Surg. Oncol., 2, 38-44. Takubo, K., Tsuchiya. S.. Fukushi. K., Shirota. A. and Mitomo, Y. (1981) Dysplasia and reserve cell hyperplasialike change in human esophagus. Acta Pathol. Jpn., 31, 999-1013. Watanabe, H.. Jass. J.R. and Solin. L. (1990) Histological Typing of Oesophageal and Gastric Tumor (second edition). Springer-Verlag. Berlin.
Squamous carcinoma
141 Ltd.
epithelial dysplasia of the esophagus
Hiroyuki Kuwano, Masayuki Watanabe, Masaki Mori and Keizo Sugimachi
associated
Noriaki
with squamous
Sadanaga,
Masahiko
cell
Ikebe,
Department of Surgery II, Facult_v of Medicine, Kyushu University, Fukuoka (Japan) (Received (Revision (Accepted
26 March 1993) received 18 May 1993) 19 May 1993)
Summary To investigate the relationship between dysplasia and carcinoma of the esophagus, 159 cases of esophageal carcinoma without any preoperative treatment were reviewed retrospectively. There were 75 dysplastic lesions in 32 cases (20.1%). The incidence of co-existence of dysplastic lesions was 0, 58.3, 31.3, 20.8 and 11.4% in intra-epithelial, mucosal and submucosal cancers and those invading the proper muscular layer and advantitia, respectively. Thus, excluding the cases of intraepithelial carcinoma, the less advanced the lesion, the higher the incidence of dysplasia. Epithelial dysplastic lesions were classified as 12 with mild, 33 with moderate and 30 with severe degrees of dysplasia. Although the continuity of dysplastic lesions to the areas of carcinoma was not so frequent (48.0%). it was more often encountered in severe dysplasia rather than in moderate or mild dysplasia, which suggested some relationship between the severity of dysplasia and carcinoma. In the cases with a dysplastic lesion the multiplicity of squamous cell carcinoma and the intra-epithelial spread of the main lesion were more frequently seen (P < O.OOl), suggesting a multicentric occurrence of dysplastic lesions and carcinomas. Correspondence 10: Hiroyuki Kuwano. Department of Surgery II, Faculty of Medicine, Kyushu University, 3-l-l Maidashi, Higashi-ku, Fukuoka 8 12, Japan.
Keywords: esophageal cancer; squamous cell carcinoma; dysplasia; carcinogenesis; multiple cancer Introduction Squamous epithelial dysplasia is frequently encountered in the esophagus with squamous cell carcinoma [9], and several studies have suggested its significance as a precancerous lesion [1,10,11,13]. Takubo et al. [16] found epithelial dysplasia of the esophageal mucosa and subclinical carcinoma in 67 (27%) and 6 (2.4%) out of 25 1 autopsied cases of non-esophageal carcinoma, respectively, and suggested that epithelial dysplasia could thus be the site of origin for cancer development. Mukada et al. [lo] revealed the progression of esophageal epithelial dysplasia towards in situ carcinoma as studied by cytofluorometric methods, using estimated Feulgen-DNA values for the histopathological grading of esophageal dysplasia. However, it has yet to be elucidated whether epithelial dysplasia in the esophagus is a pre-cancerous lesion or a co-existing lesion with esophageal cancer. In addition, the significance of the dysplasia as a histogenesis of the esophageal squamous cell carcinoma has also not yet been clearly demonstrated. Recently we performed a serial histological investigation of squamous epithelial dysplasia associated with carcinoma of the esophagus and demonstrated that many dysplastic lesions were
142
located separately from the carcinoma, and demonstrated a negative dysplasia-carcinoma sequence in many esophageal cancers [ 121. Moreover, we also collected minute foci ( < 10 mm in diameter} from the specimens of the excised esophagus and demonstrated that there was no continuity between the minute foci of carcinoma and dysplasia 131. Thus the histogenes~s of esophageal cancer is still controversial, and previous studies on lesions at an advanced stage have not been informative. In the current study we performed a serial histopathological investigation of esophageal squamous cell carcinoma, on the basis of continuity and co-existence with several degrees of epithelial dysplasia, while also directing o;lr attention to the histopathological signi~cance of epithelial dysplasia.
Materials and Methods Five hundred and fifty-two patients with primary esophageal carcinoma underwent esophageal resection in the Second Department of Surgery, Kyushu University, Fukuoka, Japan, from January 1965 to May 1991. Among these cases, excluding 393 patients with adenocarcinoma and those with gre-operative treatments, such as irradiation [ 1.41,hyperthermo-chemo-radiotherapy [ 1S] or neo-adjuvant chemotherapy, we reviewed 159 who had undergone no pre-operative treatment. Microscopic sections of the whole resected esophagus were prepared from step-sectioned blocks 5 mm wide and were stained with hematoxylin and eosin. For the histological diagnosis of squamous epithelial dysplasia we used the criteria defined by
Fig. 1. Mild dysplasia. The basal ceils in the bottom third ofthe epithelium are hyperchromatic. vary in size and demonstratemitotic activity above the level of the basement membrane (H&E. 410x ).
143
the World Health Organization’s International Histological Classification of Tumours in 1990 1171,according to which the nuclei of the lesion are enlarged and hyperchromatic while showing increased mitotic activity. In the case of mild dysplasia, such atypical nuclei are limited to the basal zone, and there is evidence of cytoplasmic maturation superficially (Fig. 1). With increasing grades of dysplasia there is a progressive increase in the proportion of atypical basal cells, until the entire thickness of the epithelium is replaced. Therefore moderate dysplasia was diagnosed when an intra-epithelial lesion similar to mild dysplasia with an atypical proliferative zone expanding up to one-half the thickness of the epithelium was found (Fig, 2). Severe dysplasia was defined as an intra~pithelial lesion with an atypical proliferative
Fig. 2.
440X).
zone encompassing up to three-quarters of the epithelium (Fig. 3). In addition, a diagnosis of intra-epithelial carcinoma was made when an epithelium was either completely or almost completely composed of atypical immature cells but lacking in invasive growth (Fig. 4). The number of various lesions were counted by a histological diagram while mapping their extent in two dimensions, and these lesions were then investigated with regard to the presence or absence of continuity to the areas of carcinoma. Clinicopathological factors were compared between the cases with and without areas of squamous epithelial dysplasia, and a chi-squared test was used for the statistical analysis.
Moderate dysplasia. An atypicat proliferative zone expanding up to one-half the :hickness of the epithelium is found (H&E.
Fig. 3.
Severe dysplasia.
An atypical
zone encompassing
up to three-quarters
Results A serial histological review of 159 specimens from patients with squamous cell carcinoma revealed 75 dysplastic lesions in 32 cases (20.1%). In three cases of intra-epithelial carcinoma (which is non-invasive carcinoma) there was no lesion of dysplasia, while 7 out of 12 cases (58.3%) with mucosal cancer (which invaded but were restricted to within the proper mucosal layer), 10 out of 32 (31.3%) with submucosal carcinoma, 5 out of 24 (20.8%) with carcinoma invading the proper muscular layer and 10 out of 88 tumors (11.4%) invaded as far as the adventitia contained areas of dysplasia in the esophagus. Thus, excluding the cases of intra-epithelial carcinoma, the less the cancer invaded, the higher the frequency of coexistence of dysplasia. There were 17 lesions of dysplasia consisting of 5 mild, 7 moderate and 5
of the epithelium
(H&E. 410
x )
with severe degrees of dysplasia in mucosal cancer, 1 mild, 10 moderate and 12 with severe dysplastic areas among 23 dysplastic lesions in submucosal cancer and 3, 8 and 17 and 3, 8 and 6 of mild to severe dysplasia in cancer invading the proper muscular layer and adventitia, respectively. Thus there were a total of 12, 33 and 30 lesions of mild, moderate and severe dysplasia, respectively (Table I). The relationship between the grade of dysplasia and the continuity to areas of carcinoma is shown in Table II. Although the frequency of continuity of the dysplasia to the carcinoma was not high (48.0%), the more severe the grade of dysplasia, the higher the frequency of continuity to the areas of carcinoma. The clinicopathological features of esophageal cancer, both with and without dysplasia, were also analyzed. There was no difference between the groups regarding age, sex distribution, location or
Fig. 4. Intra-epithelial brane (H&E, 410 x ).
carcinoma.
Co-existence
of various
Table 1.
Depth of invasion lesion
The entire thickness
degrees
of the main
of squamous
Submucosal
[31 [I21
Proper
muscular
Adventitia
Total
[321
layer
layer
epithelial
is composed
dysplasia
of atypical
cells, with an intact basement
and carcinoma.
Dysplasia Cases
Epithelium Mucosal layer
of the epithelium
~241
Lg81
[I591
0 (0) 7 (58.3)
10 (31.3)
5 (20.8)
IO (11.4)
32 (20.1)
Number
Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe
of lesions
(‘X)
5 7 5
17
IO
23
12 3 8
18
3 8 6
17
12 33 30
75
146
Table II. Continuity of dysplasia. Degrees of dysplasia (lesions)
between carcinoma
degrees
Table III. Clinicopathological with and without dysplasia.
features
of esophageal
cancer
Dysplasia
Continuity (+)
WI
and various
(-) %
Mild Moderate Severe
I331 I301
3 (25.0) 15 (45.5) 18 (60.0)
9 (75.0) 18 (54.5) 12 (40.0)
Total
[751
36 (48.0)
39 (52.0)
depth of the invasion of the main lesion, the frequencies of lymph node metastasis, the intraepithelial spread of the main lesion of esophageal cancer, lymphatic vessel permeation or vascular permeation of the carcinoma. However, the incidence of multiplicity of squamous cell carcinoma within the esophagus and the intra-epithelial spread of the main lesion was significantly higher in the group with dysplasia than in that without it (P < 0.001) (Table III).
Age Sex (M/F) Location
(+)
II= 127
n = 32
63.1 zt 9.7 107120
62.7 f 12.4 2814 % 4 (12.5) 19 (59.4) 9 (28.1)
17 (13.4) 65 (51.2) 45 (35.4)
Upper Middle Lower
Depth of invasion of the main lesion 3 (2.4) Epithelium 5 (3.9) Mucosa 22 (17.3) Submucosa 9 (15.0) Proper muscular 78 (61.4) Adventitia Lymph
Multiplicity (-) (+)
(21.9) (31.3) (15.6) (31.3)
57 (44.9) 70 (55.1)
23 (71.9) 9 (28.1)
of squamous cell carcinomab 119 (93.7) 8 (6.3)
23 (71.9) 9 (28.1)
spread
(-) (+) Lymphatic
of the main lesionbJ 73 (58.9) 4 (12.5) 51 (41.1) 28 (87.5)
vessel permeation’
(-) (+) Vascular
0 7 10 5 10
node metastasis”
(-) (+)
Intra-epithelial
To investigate the histogenesis of esophageal cancer, we demonstrated the high incidence of either glandular or mucus-secreting components in esophageal squamous cell carcinoma [4], the frequent co-existence of intra-epithelial carcinoma contiguous to the main squamous cell carcinoma in early esophageal cancer [5], the close relationship between multiplicity and the existence of intra-epithelial carcinoma with squamous cell carcinoma [6] and the high incidence of co-existence of intra-epithelial carcinoma and glandular differentiation, particularly in early cancers [7]. These results were thus thought to support the possibility of the concept of either multicentric or field carcinogenesis in esophageal cancer. To investigate the pathological significance of dysplasia as a pre-cancerous lesion, a careful chronological observation of the lesion is essential. it is quite difficult to investigate However, chronological change using biopsy specimens of human materials. Therefore the serial histopatho-
(-)
56 (45.2) 68 (54.8)
22 (68.8) 10 (31.3)
88 (71.0) 36 (39.0)
22 (68.8) 10 (31.3)
permeationC
(-) (+) “P < 0.01.
bP < 0.001. CExcluding the three with intra-epithelial
carcinoma.
logical observation of the relationship between carcinoma and dysplasia in the resected esophagus would be useful, and from this viewpont the continuity of both lesions could also be important. From the current study, as well as our recent investigations of esophageal dysplasia [3,8,12], it was demonstrated that the continuity of dysplastic lesions to the areas of carcinoma was more often
147
encountered in severe dysplasia than in moderate or mild dysplasia, although it was not frequent. We also performed a cytophatometric DNA analysis of chemically induced esophageal carcinoma in rats, and demonstrated that the biological nature of severe dysplasia might thus be considered as serious a lesion as cancer itself [2]. Although dysplasia to the carcinoma sequence could not be denied, the possibility is that severe dysplasia contiguous to the carcinoma would already have a malignant biological nature and that various degrees of dysplasia would probably occur in an esophagus containing carcinoma. The current study also demonstrated that the multiplicity of squamous cell carcinoma and the intra-epithelial spread of the main lesion of carcinoma were more frequently seen in the cases with dysplasia than in those without it. If it is assumed that an intra-epithelial lesion contiguous to the invasive cancer originates as a field effect, the various degrees of lesions such as dysplasia and carcinoma may thus occur either multicentrically or with field effects in the same esophagus and especially in those containing dysplastic lesions.
5
6
7
8
9
10
11
12
References Crepsi. M., Munoz, N., Grassi, A., Quiong, S., Jing, W.K. and Jien, L.J. (1984) Precursor lesions of oesophageal cancer in a low-risk population in China: comparison with high risk populations. Int. J. Cancer, 34, 599-602. Koga, Y., Sugimachi, K., Kuwano, H.. Mori, M. and Matsufuji, H. (1988) Cytophotometric DNA analysis of esophageal dysplasia and carcinoma induced in rats by Nmethyl-N-amylnitrosamine. Eur. J. Cancer. Clin. Oncol., 24, 643-651. Kuwano, H., Morita, M., Matsuda, H., Mori, M. and Sugimachi, K. (1991) Histopathologic findings of minute foci of squamous cell carcinoma in the human esophagus. Cancer, 68, 2617-2620. Kuwano, H., Ueo. H., Sugimachi. K.. Inokuchi. K., Toyoshima, S. and Enjoji, M. (1985) Glandular or mucus secreting components in squamous cell carcinoma of the esophagus. Cancer. 56, 5 14-5 18.
13
14
15
16
17
Kuwano, H., Matsuda, H., Matsuoka. H., Kai. H., Okudaira, Y. and Sugimachi, K. (1987) Intra-epithelial carcinoma concomitant with esophageal squamous cell carcinoma. Cancer, 59, 783-787. Kuwano, H., Ohno, S., Matsuda, H., Mori. M. and Sugimachi, K. (1988) Serial histologic evaluation of multiple primary squamous cell carcinoma of the esophagus. Cancer. 61. 1635-1638. Kuwano, H., Nagamatsu, M., Ohno, S., Matsuda, H., Mori, M. and Sugimachi, K. (1988) Coexistence of intraepithelial carcinoma and glandular differentiation in esophageal squamous cell carcinoma. Cancer, 62, 1568-1572. Kuwano, H., Baba, K., Ikebe, M., Adachi, Y., Toh, Y. and Sugimachi, K. (1993) Histopathology of early esophageal carcinoma and squamous erithelial dysplasia. Hepato-gastro Enterol.(in press). Mandard, A.M., Marnay, J., Gignoux. M., Segol, P.. Blanc, L., Olliver, J.M., Bore], B. and Mandard. J.C. (1984) Cancer of the esophagus and associated lesions: detailed pathologic study of 100 esophagectomy specimens, Hum. Pathol., 15, 600-669. Mukada, T., Sasano, N.. Sato and E. (1978) Evaluation of esophageal dysplasia by cytafluoromeric analysis. Cancer. 41, 1399-1404. Munoz, N., Crepsi, M., Grassi, A.. Qning, W.G.. Quing, S.. Cai. L.Z. (1982) Precursor lesions of oesophageal cancer in high-risk populations in Iran and China. Lancet, 17 (i), 876-879. Nagamatsu, M., Mori, M., Kuwano, H., Sugimachi, K. and Akiyoshi, T. (in press) Serial histologic investigation of squamous epithelial dysplasia associated with carcinoma of the esophagus. Cancer. Qui, S. and Yang, G. (1988) Precursor lesions of esophageal cancer in high-risk populations in Henan Province, China. Cancer, 62, 551-557. Sugimachi, K., Matsufuji, H.. Kai, H., Matsuda. H., Ueo, H. and Inokuchi, K. (1986) Preoperative irradiation for carcinoma of the esophagus. Surg. Gynecol. Obstet., 162, 544-546. Sugimachi, K. and Inokuchi, K. (1986) Hyperthermochemoradiotherapy and esophageal carcinoma. Semin. Surg. Oncol., 2, 38-44. Takubo, K., Tsuchiya. S.. Fukushi. K., Shirota. A. and Mitomo, Y. (1981) Dysplasia and reserve cell hyperplasialike change in human esophagus. Acta Pathol. Jpn., 31, 999-1013. Watanabe, H.. Jass. J.R. and Solin. L. (1990) Histological Typing of Oesophageal and Gastric Tumor (second edition). Springer-Verlag. Berlin.