Epidemiology and Clinical Aspects
Squamous carcinoma is, by far, the most common type of esophageal cancer. The disease may affect any part of the esophagus, but occurs preferentially in segments of slight narrowing: at the level of the thyroid cartilage, bifurcation of the trachea, and the diaphragm. As a general rule, fully developed esophageal cancers cause obstruction of the esophagus, resulting in difficulties of swallowing and dysphagia.
Squamous cancer of the esophagus is a quasi-endemic disorder in northeastern Iran, in parts of China, among the Chinese in Singapore, among Africans in southern Africa, and among men in Brittany (France) (Enzinger and Mayer, 2003
). In the United States, the disease is relatively uncommon; African American men appear to be more prone to it than other ethnic groups. In general, the disease is more common in males than in females. Epidemiologic data suggest that intake of hot beverages, cigarette smoking, and alcohol consumption are possible risk factors (Tavani et al, 1994
; Enzinger and Mayer, 2003
). Recent studies in China failed to reveal any consistent risk factors except, perhaps, diet (Li et al, 1989
; Yu et al, 1993
). Auerback et al (1965)
demonstrated a high frequency of squamous carcinoma in situ of the esophagus among smokers.
The prognosis of esophageal squamous carcinoma
is stage related. The overall survival is about 20% (Lerut et al, 1992
; Goldminc et al, 1993
). Izbicki et al (1997)
pointed out that the prognosis of patients with clinical stage I disease, confined to the wall of the esophagus, may be modified by finding occult micrometastasis
in regional lymph nodes stained with an epithelial antibody. Stockeld et al (2002)
described the use of fine needle aspiration (FNA) biopsy technique
for prognosis of esophageal squamous cancer. Aspirates of the esophageal wall, obtained at 2 cm intervals, led to the discovery of microscopic tumor spread in onethird of the 52 investigated patients. The results were more accurate than synchronous esophageal brushing or multiple biopsies. The ratio of benign to malignant cells in the aspirated samples appeared to be of prognostic significance.
Kwong et al (2004)
studied chromosomal aberrations in esophageal squamous cancer by comparative genomic hybridization. Numerous gains and losses were observed but gain in the short arm of chromosome 12
(+ 12p) predicted poor prognosis after surgery, at least among the Chinese.
Adenocarcinoma occurring in Barrett’s esophagus is discussed below.
Human Papillomavirus in Squamous Cancer of the Esophagus
Invariably, as with all squamous cancers, the question of human papillomavirus (HPV) as a factor in the genesis of this tumor
was raised (Syrjänen, 1987
). HPV DNA presence in five invasive esophageal cancers was first reported by Kulski et al (1986). Subsequently, Chang et al (1992)
reported the presence of HPV in 25 of 51 (49%) biopsies
from Chinese patients with invasive esophageal carcinoma. In 16 of these 25 specimens, HPV types 16 and 18 were documented by in situ hybridization. Other types of HPV were observed in the remaining 7 patients. In the same study, 53 of 80 cytologic preparations,
also from asymptomatic Chinese patients from a high-risk area, were positive for HPV by filter in situ hybridization. HPV was also detected in cells of 2 of 9 patients without cytologic abnormalities, in 3 of 6 patients with “mild dysplasia,” in 25 of 31
patients with “moderate dysplasia,” in 19 of 28 patients with “severe dysplasia,” and in 4 of 6 patients with invasive carcinoma. In an update of this study, Chang et al (2000)
reported that 16.9% of 700 Chinese patients with esophageal carcinoma were HPV positive, with 27% of the positive samples containing the “high risk” HPV types 16 and 18.
Figure 24-5 Squamous cancer of the esophagus. A. Composite image of well differentiated squamous cancer cells observed in typical squamous carcinoma of the esophagus. The cancer cells are markedly keratinized and have obvious enlarged hyperchromatic nuclei. B. Invasive squamous carcinoma of the esophagus corresponding to A. C. Poorly differentiated squamous carcinoma of the esophagus. The tumor cells are smaller and show marked nuclear abnormalities. D. Tissue lesion corresponding to C. (A: Images obtained by PAPNET apparatus. With permission of TriPath Imaging, Burlington, NC.)
It is quite evident that the issue of the role of HPV in esophageal carcinoma has not been definitely settled but there appears to be little doubt that in tumors from some patients, mainly Chinese and Japanese, the virus is present (Galloway and Daling, 1996
). Since a person-to-person transmission of HPV is unlikely in these patients, an activation of the latent viral infection is a more likely explanation of these findings.
It is of note that Wang et al (1999)
detected Epstein-Barr virus (EBV)
in squamous cancer in Taiwan.
As discussed above, these tumors may occur in a variety of grades and degrees of differentiation. The cytologic findings in esophageal washings or brushings closely reflect these structural variants and are similar to those described for bronchogenic carcinomas of similar histologic types (see Chap. 20
The well-differentiated squamous carcinoma
produces heavily keratinized abnormal squamous cells, singly or in clusters, with either completely pyknotic, hyperchromatic nuclei, or with nuclear shadows,
much in the manner described for similar cancers of the bronchus (Fig. 24-5A
; see Chap. 20
). Koilocyte-like cells
with large, hyperchromatic nuclei and perinuclear clear zones or halos are sometimes observed in such tumors. There is no good correlation between these cells and the presence of HPV.
Figure 24-6 Poorly differentiated squamous (epidermoid) carcinoma and small cell esophageal cancer. A. Esophageal balloon sample shows a cluster of cancer cells from an occult epidermoid carcinoma of the esophagus shown in B. C. Composite images of a small-cell (oat cell) carcinoma of the esophagus. Note the very small cancer cells forming clusters and sheets. D. Basaloid carcinoma of the esophagus composed of small cells. In spite of its orderly appearance, this tumor is highly malignant. (C: Images obtained with the PAPNET apparatus. With permission of TriPath Imaging, Burlington, NC.)
Less well-differentiated squamous cancers of large cell type (epidermoid carcinomas)
are characterized by smaller cancer cells with very scanty basophilic cytoplasm, often forming clusters,
particularly in brush specimens (Figs. 24-5C
). The nuclear abnormalities in the form of enlargement, hyperchromasia and large nucleoli
are usually quite evident. The diagnosis of tumor type depends largely on the finding of squamous cancer cells with eosinophilic cytoplasm, which may be very scarce.
Small cell carcinomas,
the most anaplastic varieties of squamous cancer,
produce cancer cells that often are very small, with abnormally large, hyperchromatic nuclei and very scanty cytoplasm
). The corresponding tissue sections may sometimes show the “basaloid” tumor pattern (Fig. 24-6D
). Horai et al (1978)
, Reid et al (1980)
, and Imai et al (1978)
described several examples of such carcinomas. Hoda and Hajdu (1992)
pointed out that, contrary to oat cell carcinoma of the bronchus, cell molding was uncommon in the esophageal tumors
and that the evidence of endocrine activity
in these tumors was insecure.
Squamous or epidermoid carcinomas of the distal end of the esophagus
may extend into the gastric cardia and fail to produce radiographic abnormalities of cancer on cursory examination.
Cytologic examination, either by esophageal or gastric brushings, may be of critical diagnostic importance (Fig. 24-7
The use of fine needle aspiration of the esophageal wall, for diagnosis and prognosis of squamous cancer, proposed by Stockeld et al (2002)
was described above.
Precursor Lesions of Squamous Carcinoma and Their Detection: Lessons From China
In the 1961 and 1968 editions of this book, it was anticipated that carcinoma of the esophagus must be preceded by precancerous epithelial changes, such as carcinoma in situ and related abnormalities.
In the Western world, the knowledge of precancerous squamous lesions of the esophagus is scarce. There are several cases on record in which squamous carcinoma in situ
and related lesions had been observed as incidental findings (previous editions of this book; Imbriglia and Lopusniak, 1949
; Auerback et al, 1965
; Ushigome et al, 1967
; Koss et al, 1998
) or as a lesion accompanying invasive carcinoma (Suckow et al, 1962
; Kuwano et al, 1988
). However, the hypothesis could be confirmed only by the extensive cytologic and histologic studies of esophageal cancer conducted by Chinese investigators.
Figure 24-7 Poorly differentiated squamous carcinoma involving distal esophagus and adjacent gastric cardia. The tumor was roentgenologically occult. A,B. Clusters of small malignant squamous cells in esophageal lavage. C. Squamous carcinoma in situ involving lower esophagus with transition to invasive carcinoma, shown in D.
The stimulus for the Chinese studies was the very high prevalence rate of esophageal cancer in certain areas of central and northern China
; Shu 1984
). It is of incidental interest that, in the same areas of China, chickens are susceptible to cancer-like tumors of the gullet.
The relationship of these tumors to human cancer is not understood. Except for its possible association with diet and human papillomavirus, the causes of human esophageal cancer in China and its relationship to the tumors in poultry, remain unknown at the time of this writing (2004).
The Chinese investigators proposed that prevention of esophageal cancer could be based on the same principles as detection of precursor stages of cancer of the uterine cervix.
If cytologic samples, obtained in asymptomatic, high-risk populations, could lead to the discovery of precancerous lesions, then early surgical intervention
or photodynamic therapy
could prevent invasive esophageal cancer with its very high mortality rate (Yang et al, 2002
). The instruments
used in the cytologic investigations were small,
inflatable plastic balloons with abrasive surface
), modifications of a gastric balloon that was described in 1950 by Panico et al. The balloon was attached to a narrowcaliber tube with color markers to indicate the position of the balloon in the esophagus. The balloon could be easily swallowed in deflated state, moved by peristalsis to the cardia, inflated, and slowly withdrawn to the level of the cricoid cartilage. At this point, the balloon is deflated and withdrawn. The abrasive surfaces of the balloon contained cells scraped from the surface epithelium that could be examined in smears. The method, which was tested in our institution, caused trivial discomfort to the patients and was well accepted (Greenebaum, 1984
Figure 24-8 Esophageal balloon, collapsed (bottom) and distended with air (top). Note the rugosity of the surface that serves to obtain cell samples from the esophagus. The balloon is connected to a plastic tube with markers to indicate the position of the balloon in the esophagus. (Courtesy of Dr. Yi-Jing Shu, St. Gallen, Switzerland.)
The accuracy of balloon sampling
was tested in China on 1,861 patients with overt esophageal cancer, documented by biopsy. The accuracy varied from 87.2% to 99.0%, averaging 94.9% (summary in Shu 1984
). As reported by Shu in 1984
, the cytologic sampling by balloon proved to be much superior to either endoscopy or radiologic examination for the diagnosis of precursor lesions and early invasive squamous carcinoma.
In an elaborate statistical analysis, Dawsey et al (1994A
compared the results of cytologic sampling with the incidence rates of esophageal squamous carcinoma
in the Linxian province of China and concluded that the esophageal balloon cytology successfully identified persons at increased risk for esophageal cancer.
This was confirmed for the Anyang County of China by Yang et al (2002)
. It is not known how the balloon method would compare with contemporary endoscopy, which because of cost and limited availability could not be used on a very large scale for purposes of esophageal cancer detection.
Several other methods
to study esophageal cytology were developed. Jaskiewicz et al (1987)
used a small sponge, attached to a string and packaged in an easy-to-swallow gelatin capsule
to study patients in South Africa. A similar system was described by Sepehr et al (2000)
as better acceptable to patients. Qin and Zhou (1992)
described an elastic plastic tube
for esophageal sampling and reported an accuracy of 96% in the diagnosis of cancer.
Results of Screening
The first results of the population survey were presented in the Fourth International Cancer Congress in Florence, Italy in 1974 by an anonymous group representing the Chinese Academy of Medical Sciences. A cytologic survey of 17,471 persons over 30 years of age was conducted in the Henan Province in northern China. “Dysplasia”
of the esophageal epithelium was observed in 276 patients, mostly below the age of 40, whereas invasive carcinoma in this population usually occurred in patients older than 40. Follow-up study of the patients with “dysplasia,”
some over a period of 7 to 10 years, disclosed that 30.3% of them developed esophageal carcinoma, in 27.3% the original lesion persisted unchanged, and in 42.4% the changes either regressed to mild dysplasia or reverted to normal. In histologic studies of 67 patients, the progression of dysplasia of various types to carcinoma in situ could be observed in many specimens.
It was the conclusion of this study that “marked dysplasia” must be considered a precancerous lesion.
During the intervening years and changing political conditions in China, the names of the investigators became known (summary in Shu 1984
, and the results of several surveys became available.
As related by Shu in 1984
, there is no doubt that mass screening for esophageal carcinoma in high-risk areas of-China had a major beneficial effect. Before screening was instituted, the diagnosis of carcinoma in situ or early invasive carcinoma was 2 per 1,000 in low-risk areas and 10 per 1,000 in high-risk areas. Screening of 81,187 asymptomatic people over the age of 30 in the high-risk Henan Province resulted in the discovery of 880 esophageal cancers (a huge prevalence rate of 1%!
), of which 649 (73.7%) were early and treatable by surgery (Shu, 1984
). Less is known about survival of these patients, but Dr. Shu assured me that most of the treated patients survived 5 years or longer with a good quality of life. This information must be compared with a survival of about 10% to 25% of patients with invasive squamous cancer of the esophagus commonly observed in the Western world (Ide et al, 1994
; Lieberman et al, 1995
). Kwong et al (2004)
reported that, among Chinese patients with esophagus cancer, those showing a gain of the short arm of chromosome 12
(+p12) in the tumor had poor outcome after surgical treatment, regardless of stage of disease.
Screening for Esophageal Squamous Cancer in Countries Other Than China
The accomplishments of the Chinese scholars found several imitators. Thus, Berry et al (1981)
attempted a similar project in South Africa (where the rate of esophageal cancer is very high among some black populations), resulting in the discovery of 15 occult invasive carcinomas and carcinomas in situ in 500 patients studied. Dysplasia was illustrated, but the clinical significance of the lesion was not discussed. Similar results were reported by Jaskiewicz et al (1987)
from a high-risk rural population in Transkei (South Africa); in
five patients, dysplastic changes progressed to invasive cancer.
To our knowledge, the Chinese experience has not been duplicated in the Western countries, except for the work in this laboratory. Greenebaum et al (1984)
studied 96 high-risk Montefiore Hospital patients in New York City by the balloon technique. The selected patients had prior cancers of the larynx or pharynx, or were alcoholics and heavy cigarette smokers. Greenebaum unexpectedly found three occult recurrent oropharyngeal cancers and one carcinoma in situ of the esophagus, observed in a man with prior history of squamous carcinoma of the larynx.
The biopsy of the esophagus disclosed fragments of squamous cancer in the absence of radiologic abnormalities.
Classification of Precancerous Lesions in China
Based on cytologic and histologic criteria, the Chinese investigators divided the precancerous lesions into two groups: dysplasia and carcinoma in situ. The criteria were derived from the classification of precancerous lesions of the uterine cervix
(see Chap. 11
). Lesions with more orderly epithelial growth, surface differentiation, and relatively minor nuclear abnormalities were classified as dysplasia and lesions with more significant atypia were classed as carcinoma in situ.
The dysplasias were further subdivided into mild, moderate, and severe, based mainly on cytologic criteria
(see below). The true significance of dysplasia is not clear. Although, in some patients, the lesions either failed to progress or regress, there is no doubt that, in a substantial number of untreated patients, invasive cancer of the esophagus was subsequently observed
). The same conclusion was reached by Sugimachi et al (1995)
, who considered “dysplasia” as an early carcinoma of the esophagus. In any event, the insecure behavior of the precancerous lesions of the esophagus is remarkably similar to lesions of the uterine cervix
(see Chap. 11