Analysis of clinical features of 261 cases of early esophageal cancer with leukoplakia as the main manifestation

doi:10.21203/rs.3.rs-4693236/v1

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Analysis of clinical features of 261 cases of early esophageal cancer with leukoplakia as the main manifestation

https://doi.org/10.21203/rs.3.rs-4693236/v1

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Summarize and analyze the clinical characteristics of early esophageal cancer mainly manifested by leukoplakia.The clinical features between complete leukoplakia type and mixed type of early esophageal cancer have some differences as well as commonalities in the meantime. The lesions have clear borders, irregular patterns, and uneven thickness of leukoplakia, which occur mostly in the background of the mottled esophagus, and the location of the lesions is predominantly in the middle and lower parts of the esophagus. Pathologic findings of complete leukoplakia-type lesions were predominantly low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia (M1), and mixed lesions were predominantly high-grade intraepithelial neoplasia (M1) and intra-intrinsic invasive squamous cell carcinoma (M2). Complete leukoplakia-type lesions are relatively young and the lesion area is smaller than that of mixed lesions, the lesion morphology is mostly IIa, the surface IPCL is mostly invisible under NBI magnification, and the Lugol's iodine staining is lightly stained or unstained. Mixed lesions tend to occur in older patients, the lesion area is larger than the other, the lesion morphology tends to show IIa + IIb, NBI magnification of the surface IPCL is more likely to be visible, and Lugol's iodine staining tends to be unstained.

Health sciences/Gastroenterology

Health sciences/Signs and symptoms

Early esophageal cancer

Leukoplakia

Esophageal cancer is a common malignant tumor that originates from the human esophageal mucosal epithelium. Among malignant tumors, esophageal cancer accounts for the 8th highest incidence rate and the 6th highest mortality rate¹.The morbidity and mortality rates are two to three times higher in men than in women². The pathological types of esophageal cancer are mainly categorized into two types, squamous cell carcinoma, and adenocarcinoma, with significant differences in incidence and mortality in different countries and regions, with squamous cell carcinoma predominating in East Asia, such as China, where the incidence rate is high, and adenocarcinoma in Europe and the United States, where the incidence rate is relatively high³.

The prognosis of esophageal cancer is closely related to clinical stages. The 5-year survival rate of progressive esophageal cancer is still less than 30% even after comprehensive treatments such as surgery, radiotherapy, and chemotherapy, while the 5-year survival rate of early esophageal cancer can reach more than 90% after minimally invasive treatments such as endoscopic submucosal dissection (ESD)^4–8.Therefore, early diagnosis and treatment of esophageal cancer are crucial. Currently, the vast majority of endoscopic and pathological features of early esophageal cancer described in the literature are summarized based on early esophageal cancers presenting with a reddish background, and little is known about the endoscopic and pathological features of early esophageal lesions predominantly presenting with leukoplakia. The current literature presents only a small number of case reports of leukoplakia-type early esophageal cancer, and there is no extensive and systematic clinical data summary and description^9–13. Endoscopists and pathologists have a low level of diagnosis of this type of early esophageal lesion without uniform standards, which can easily lead to misdiagnosis and missed diagnosis. The purpose of this paper is to analyze and summarize the clinical characteristics of early esophageal cancer with leukoplakia as the main manifestation, and to try to guide endoscopists and pathologists in recognizing this type of lesion, to avoid misdiagnosis and underdiagnosis and missed diagnosis.

General information

We retrospectively collect and analyze the endoscopic, pathological, and clinical data of patients with early esophageal cancer presenting mainly as leukoplakia, who accepted esophageal endoscopic submucosal dissection (ESD) from January 2014 to January 2024 in the Second Hospital of Shandong University. Inclusion criteria: (1) Early esophageal cancer presenting as complete leukoplakia type, or mixed leukoplakia and erythema type, but predominantly leukoplakia, i.e., the leukoplakia accounted for more than 1/2 of the main body of the lesion; (2) preoperative evaluation meeting the indications for ESD, and concomitant ESD treatment; and (3) the endoscopic, pathological, and clinical data were complete. Exclusion criteria: (1) early esophageal cancer with leukoplakia as the main manifestation but without ESD treatment; (2) early esophageal cancer with leukoplakia as the main manifestation failed to achieve en-bloc resection despite ESD treatment; and (3) incomplete endoscopic, pathologic, and clinical data.

Baseline statistics

A total of 261 cases of early esophageal cancer with leukoplakia as the main manifestation met the criteria, and the following data of the 261 cases were counted separately: age, sex, smoking history, drinking history, lesion location, lesion morphology, regularity of the leukoplakia morphology, uniformity of the thickness of the leukoplakia, clearness of the border of the lesion, whether the lesion was combined with erythema, the manifestation of the Lugol's iodine staining, the long diameter of the lesion, the short diameter of the lesion, the visibility of the IPCL, the typology of the IPCL, whether the background of the esophagus was spotted, and the pathologic results, etc.

Statistical methods

SPSS 25.0 software was used to process the data. Measurement data were tested by the Shapiro-Wilk normality test, and those conforming to normal distribution were expressed as (x̅±s). Between-groups analysis of independent samples was performed by t-test, and between-groups analysis of count data was performed by X² test. P < 0.01 will be regarded as a statistically significant difference.

Baseline information

The average age of the 261 patients was 60.97 ± 8.12; the average long diameter of the lesions was 1.70 ± 1.00 CM and the average short diameter was 1.06 ± 0.57 CM; among them, 177 were male and 84 were female; 142 had a history of smoking and 119 didn't; 151 had a history of alcohol consumption and 110 didn't. there were 147 cases of complete leukoplakia-type lesions and 114 cases of mixed-type lesions. As for lesion morphology, 90 cases showed IIa, 19 cases IIb, and 152 cases IIa + IIb. There are 243 cases with clear lesion boundaries and 18 cases with unclear boundaries. IPCL was not visible in 101 cases and was visible in 160 cases under NBI magnification, of which those with visible IPCL all showed B1 type. The leukoplakia of all lesions are irregular in shape and uneven in thickness. Lugol's iodine staining showed light staining in 72 cases, no staining in 139 cases, and 50 patients did not undergo Lugol's iodine staining. The background of the esophagus was mottled esophagus in 196 cases and non-mottled esophagus in 65 cases; the lesions were located in the upper esophagus in 23 cases, the middle esophagus in 121 cases, and the lower esophagus in 117 cases. Pathologically, there were 39 cases of low-grade intraepithelial neoplasia; 144 cases of high-grade intraepithelial neoplasia (M1); and 78 cases of intrinsic invasive squamous cell carcinoma (M2). Table 1 shows the Baseline information on early esophageal lesions with leukoplakia as the main manifestation.

Table 1

Baseline information on early esophageal lesions with leukoplakia as the main manifestation
baseline information	Categories	Number of cases	Average values (x̅±s)
Age	—	—	60.97 ± 8.12
Long diameter of the lesion (CM)	—	—	1.70 ± 1.00
Short diameter of the lesion(CM)	—	—	1.06 ± 0.57
Sex	male	177
	female	84
Smoking history	current/past smoker	142
	never smoker	119
Drinking history	current/past drinker	151
	never drinker	110
Lesion coloration	complete leukoplakia type	147
	mixed type	114
Morphology of lesions	IIa	90
	IIb	19
	IIa + IIb	152
Lesion border	well-defined border	243
	no clear border	18
IPCL	invisible	101
	visible	160
Morphology of the leukoplakia	regular	0
	irregular	261
Thickness of the leukoplakia	even	0
	uneven	261
Lugol's iodine staining	lightly stained	72
	unstained	139
	undone	50
Esophageal background	mottled esophagus	196
	non-mottled esophagus	65
Lesion location	upper of the esophagus	23
	middle of the esophagus	121
	lower of the esophagus	117
pathological findings	low-grade intraepithelial neoplasia	39
	high-grade intraepithelial neoplasia(M1)	144
	Intrinsic intramembranous invasive squamous cell carcinoma(M2)	78

The 261 lesions were divided into two subgroups, complete leukoplakia type and mixed type, according to the color of the lesions, and the characteristics of endoscopic, pathological and clinical data between the two groups were statistically analyzed separately. Table 2 shows the Endoscopic, pathologic, and clinical characteristics of the complete leukoplakia type group and the mixed type group.

Table 2

Endoscopic, pathologic, and clinical characteristics of the complete leukoplakia type group and the mixed type group.
Baseline information	Categories	complete leukoplakia type	Mixed type	P	Statistical methods
Age		59.69 ± 7.88	62.62 ± 8.19	<0.01	t-test
Long diameter of the lesion (CM)		1.29 ± 0.66	2.22 ± 1.13	<0.01	t-test
Short diameter of the lesion(CM)		0.87 ± 0.43	1.31 ± 0.63	<0.01	t-test
Sex	male	107	70	0.051	X² test
	female	40	44
Smoking history	current/past smoker	81	61	0.798	X² test
	never smoker	66	53
Drinking history	current/past drinker	89	62	0.318	X² test
	never drinker	58	52
Morphology of lesions	IIa	90	0	<0.01	X² test
	IIb	8	11
	IIa + IIb	49	103
Border of lesions	clear	141	102	0.042	X² test
	unclear	6	12
IPCL	visible	46	114	<0.01	X² test
	invisible	101	0
Morphology of the leukoplakia	regular	0	0	—	—
	irregular	147	114
Thickness of the leukoplakia	even	0	0	—	—
	uneven	147	114
Lugol's iodine staining	lightly stained	64	8	<0.01	X² test
	unstained	50	89
	undone	33	17
Esophageal background	mottled esophagus	106	90	0.205	X² test
	non-mottled esophagus	41	24
Lesion location	upper of the esophagus	12	11	0.038	X² test
	middle of the esophagus	59	62
	lower of the esophagus	76	41
pathological findings	low-grade intraepithelial neoplasia	33	6	<0.01	X² test
	high-grade intraepithelial neoplasia(M1)	82	62
	Intrinsic intramembranous invasive squamous cell carcinoma(M2)	32	46

The average age of the patients in the complete leukoplakia type group was 59.69 ± 7.88, and the mean age in the mixed type group was 62.62 ± 8.19, with statistical differences between the groups;

In the complete leukoplakia type group, the average long diameter of the lesion was 1.29 ± 0.66 CM, and the average short diameter was 0.87 ± 0.43 CM; in the mixed type group, the average long diameter of the lesion was 2.22 ± 1.13 CM, and the average short diameter was 1.31 ± 0.63 CM, with statistical differences between the groups;

There were 107 male patients and 40 female patients in the complete leukoplakia type group, and 70 male patients and 44 female patients in the mixed type group, with no statistical difference between the groups;

There were 81 patients with a history of smoking and 66 patients without a history of smoking in the complete leukoplakia group, and 61 patients with a history of smoking and 53 patients without a history of smoking in the mixed group, with no statistical difference between the groups;

There were 89 patients with a history of alcohol consumption, and 58 patients without in the complete leukoplakia type group, 62 patients with a history of alcohol consumption, and 52 patients without in the mixed type group. There is no statistical difference between groups;

The lesions in the complete leukoplakia group showed 90 cases of IIa, 8 cases of IIb, and 49 cases of IIa + IIb, and the lesions in the mixed group showed 0 cases of IIa, 11 cases of IIb, and 103 cases of IIa + IIb, with statistically significant differences between the groups;

There were 141 cases with clear lesion borders and 6 cases with unclear lesion borders in the complete leukoplakia group, 102 cases with clear lesion borders, and 12 cases with unclear lesion borders in the mixed group, with no statistical difference between the groups;

Both the complete white spot group and the mixed group showed irregular white spot patterns and uneven white spot thickness;

As for Lugol's iodine staining, the complete leukoplakia group showed 64 cases of light staining, 50 cases of no staining, and 33 cases of no iodine staining; the mixed group showed 8 cases of light staining, 89 cases of no staining, and 17 cases of no iodine staining, with statistical differences between the groups;

There were 106 cases of esophageal background manifesting as mottled esophagus and 41 cases of non-mottled esophagus in the group of complete leukoplakia type, and 90 cases of mottled esophagus and 24 cases of non-mottled esophagus in the group of mixed type, and there was no statistically significant difference between the groups;

In the complete leukoplakia group, 12 lesions were located in the upper esophagus, 59 in the middle esophagus, and 76 in the lower esophagus, while in the mixed group, 11 lesions were located in the upper esophagus, 62 in the middle esophagus, and 41 in the lower esophagus, and there was no statistically significant difference between the groups;

There were 33 cases of low-grade intraepithelial neoplasia in the complete leukoplakia group, 82 cases of M1, 32 cases of M2, and 6 cases of low-grade intraepithelial neoplasia in the mixed group, 62 cases of M1, and 46 cases of M2, with a statistically significant difference between the groups.

Case 1

Low-grade intraepithelial neoplasia

Figure1.Endoscopy Description: A flaky leukoplakia was seen in the esophagus (32CM from the incisors), about 1.0*0.6 CM in size, with clear borders, irregular morphology, uneven thickness, and cloudy surface; IPCL was not visible after NBI Magnifying Endoscopy, and it showed a light stain after Lugol's iodine staining.

Figure2 (a,b). 1–2 layers of cells at the base of the mucosa were densely arranged, with an enlarged nucleoplasm ratio, eosinophilic cytoplasm, and growing downward in a angle of emergence way, with a distinct granular layer and significant keratinization of the mucosal surface, and a low-grade intraepithelial neoplasia manifestation.

Case 2

High-grade intraepithelial neoplasia

Figure3.Endoscopy Description: In the esophagus (38CM-40CM from the incisors), a flaky leukoplakia was seen, about 1.5*1.0CM in size, with clear borders, irregular morphology, uneven thickness, cloudy surface, biopsy scar was seen on the anal side, IPCL was not visible after NBI Magnifying Endoscopy, and iodine staining was unstained.

Figure4. (a,b). Squamous epithelial cells with significant heterogeneity were located in the lower 1/2 layer of the mucosa, with a marked tendency to grow downward, and the superficial layer of the mucosa appeared to have a distinct granular layer and significant keratinization, presenting as high-grade intraepithelial neoplasia (M1).

Case 3

High-grade intraepithelial neoplasia (M1) and localized invasive squamous cell carcinoma within the lamina propria (M2)

Figure5.Endoscopy Description: In the esophagus (31CM-33CM from the incisors), a roughly patchy mucosa was seen, with a mixture of leukoplakia and erythema, with leukoplakia predominantly, and areas of erythema were seen at the edges and central part, measuring about 1.7*1.7CM.The leukoplakia was irregular in morphology, uneven in thickness, with a cloudy surface, IPCL was not visible at the leukoplakia after NBI Magnifying Endoscopy and was visible at the erythematous spots in a B1 pattern, and Lugol's iodine staining showed unstained.

Figure6. (a). Comparison of leukoplakia and erythematous area, the right side of the picture represents the leukoplakia area and the left side represents the erythematous area. (b,c). On the leukoplakia area, the squamous epithelial cells with significant heterogeneous rows exceeded 1/2 layer of the mucosa, and there were increased nucleated cells in the superficial layer of the mucosa, with obvious eosinophilic cytoplasm, and keratinized granules were seen, presenting the change of keratosis imperfect. (d,e). On the erythema area, the squamous epithelial cells of the whole layer showed significant heterogeneous rows, and the vascular papillae were upwardly prolonged. High-grade intraepithelial neoplasia (M1) and localized invasive squamous cell carcinoma within the lamina propria (M2) were present.

Early esophageal cancer and precancerous lesions are the early stages of progressive esophageal cancer, and their prognosis is significantly improved compared with that of progressive esophageal cancer, so early diagnosis and early treatment by digestive endoscopy are of great significance. Early esophageal cancer and precancerous lesions can be treated by endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR), multiband mucosectomy (MBM), endoscopic radiofrequency ablation (ERFA), and other endoscopic methods of minimally invasive treatment with less trauma and good therapeutic effect. The most obvious advantage of ESD, compared with other methods, is that it can realize en-bloc resection, reduce the residual lesion, improve the cure rate, and it can also provide complete pathological specimens, and improve the accuracy of postoperative pathological staging diagnosis. It is a standard treatment for early esophageal cancer and precancerous lesions^{14, 15}. The characteristics of early esophageal cancer and precancerous lesions described in the literature are almost always summarized based on cases with a reddish background and visible IPCL, and the type of lesion and depth of infiltration can be accurately determined by IPCL classification^{11, 16–18}. However, early esophageal cancers with leukoplakia in the background show unclear or invisible IPCL on the surface, and it is not possible to judge the nature of the lesions by traditional IPCL typing. The characteristics of these lesions have only been described in a few case reports, which are not supported by a large number of case data, and there is no uniform diagnostic standard yet^19–21. Endoscopists and pathologists have insufficient knowledge of such lesions, which can lead to misdiagnosis and underdiagnosis. In this paper, we summarize for the first time the clinical characteristics based on a large number of early esophageal cancers with leukoplakia as the main manifestation and generalize the endoscopic and pathological manifestations of such lesions. This is of significant value in guiding endoscopists and pathologists in improving their diagnostic capabilities for such lesions and reducing misdiagnoses and missed diagnoses.

In this study, we divided 261 cases of early esophageal cancer that met the inclusion criteria into two subgroups according to the color of the lesions, i.e., complete leukoplakia type and mixed type (both leukoplakia and erythema are present), and counted the differences in endoscopic, pathologic, and other clinical characteristics between the two groups separately.For endoscopic classification of lesion morphology, we use the Paris classification²², and for IPCL classification, we use the JES classification developed by the Japanese Esophageal Society¹⁸. Mottled esophagus is defined as patches of lightly stained or unstained areas in the whole or most of the esophagus after Lugol's iodine staining, or multiple patches of brown areas under optical staining, such as NBI, and is considered to be a high-risk factor for the development of esophageal cancer.By analysis, there was no statistical difference between the two groups in terms of sex, smoking history, alcohol history, lesion boundaries, esophageal background, and lesion location, and there were statistically significant difference between the two groups in terms of age, lesion length, lesion short diameter, lesion morphology, whether or not surface IPCL was visible, presentation after Lugol's iodine staining, and pathological results. The common features of complete leukoplakia and mixed lesions are that they occur more often in males, with smoking and drinking habits, and their lesions have clear borders, irregular leukoplakia morphology, uneven thickness of leukoplakia, occurring more often in the background of mottled esophagus, and the location of the lesions is predominantly in the middle and lower parts of the esophagus. Pathologic results of complete leukoplakia-type lesions were predominantly low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia (M1), and mixed-type lesions were predominantly high-grade intraepithelial neoplasia (M1) and intra-intrinsic invasive squamous cell carcinoma (M2). In the complete leukoplakia type lesion, the age of onset is relatively young, the lesion area is smaller than the mixed lesion, the lesion morphology is mostly IIa, the surface IPCL tends to be invisible under the magnification of NBI, and the results of the Lugol's iodine stain is often slightly stained or unstained. On the contrary, mixed-type lesions tend to occur in older patients, the lesion area is larger than that of complete leukoplakia-type lesions, and the lesion morphology tends to show IIa + IIb, and the surface IPCL is more likely to be visible after magnified observation by NBI, and all of them show type B1 when IPCL is visible in the included cases, and they tend to be unstained after Lugol's iodine stain. Through the analysis of the above characteristics, we found that the mixed lesions are larger in size and more severe than the complete leukoplakia-type lesions, from which we presumed that the mixed lesions may be the result of the further development of the complete leukoplakia-type lesions and during the progression of the lesion, the leukoplakia areas may gradually become thinner and may peel away. So that, mucosal surface IPCL gradually become visible. Complete leukoplakia type lesions may be an early stage of mixed type lesions, but whether there is a progression pattern of complete leukoplakia lesion-leukoplakia and erythematous mixed lesion-erythematous lesions still needs to be further studied, and a large amount of clinical data needs to be accumulated to support it.

Esophageal leukoplakia is a patchy lesion of the esophageal mucosa, with a low incidence of less than 1% in the esophagus, characterized pathologically by metaplasia and hyperkeratosis of stratified squamous epithelium, and must be differentiated from glycogen acanthosis, inflammatory leukoplakia, papillomas, etc^{21, 23, 24}. Studies on esophageal leukoplakia are rare, and the mechanisms that cause it to develop and regress clinically are unknown. With the deepening understanding of this lesion, some scholars have found that some of the esophageal leukoplakia has the potential for malignant transformation and is a precancerous state of esophageal squamous cell carcinoma^25–29. Early esophageal lesions of the complete leukoplakia type are initially pathologically characterized as atypia of the basal cell. As the lesion progresses, cellular atypia and structural atypia become apparent, with gradual involvement of the epithelium^{30, 31}. How to identify whether leukoplakia is early esophageal cancer by its gastroscopic appearances༟ In an effort to provide relatively better guidance to endoscopists for accurate diagnosis of leukoplakia-type early esophageal cancer, we have characterized the endoscopic features of leukoplakia-type early esophageal cancer as follows. 1. the border of the leukoplakia is clear; 2. the shape of the leukoplakia is irregular; 3. the surface of the leukoplakia is not smooth, the thickness is not uniform, the surface has cloudy changes, and the IPCL at the leukoplakia is not visible after the NBI magnification; 4. When there is erythema in the leukoplakia area, the erythema is often located in the peripheral area and the relatively thin area of the leukoplakia, the IPCL is usually visible at the erythema, and the IPCL can be used at this time to judge the type of lesion and the depth of infiltration; 5. Lugol's iodine staining shows light staining or no staining; 6. The diameter of leukoplakia is greater than 1CM. The more the leukoplakia meets the above characteristics, the greater the possibility that it may be diagnosed as early esophageal cancer.

In this article, we analyzed and summarized the endoscopic, pathological, and other clinical features of leukoplakia-type early esophageal cancer, and for the first time, we proposed the characteristics of gastroscopic manifestations of this type of lesion. However, in the future, more supporting clinical cases and further studies are expected to reveal the connection and difference between leukoplakia-type early esophageal cancer and erythema-type early esophageal cancer.

Competing Interests:

Authors declare no conflict of interests for this article.

Ethics Declarations

This study was approved by the institutional ethics committee of the Second Hospital of Shandong University (No:…)and written informed consent was obtained from all patients before enrollment. The guidelines tlined in the Declaration of Helsinki were followed and this manuscript adhered to the applicable CONSORT guidelines.The guidelines tlined in the Declaration of Helsinki were followed and this manuscript adhered to the applicable CONSORT guidelines.

Author Contribution

Guang-chun Li was responsible for designing the review protocol, writing the protocol and report, conducting the search, screening potentially eligible studies, extracting and analysing data, interpreting results, updating reference lists and creating ’Summary of findings’ tables. Xing Qi and Jiang-ying Kuang was responsible for designing the review protocol and screening potentially eligible studies. She contributed to writing the report, extracting and analysing data, interpreting results and creating ’Summary of findings’ tables. Yu-ping Zheng、Zhao-sheng 、Zhen Zhang and Dong-dong Zhang Chenconducted the meta-regression analyses and contributed to the design of the review protocol, writing the report, arbitrating potentially eligible studies, extracting and analysing data and interpreting results. Jian-qiang Guo and Hong-lei Wu contributed to data extraction and provided feedback on the report.

Data Availability

Data is provided within the manuscript .

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Analysis of clinical features of 261 cases of early esophageal cancer with leukoplakia as the main manifestation

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Abstract

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Introduction

Materials and Methods

General information

Baseline statistics

Statistical methods

Results

Baseline information

Discussion

Declarations

Competing Interests:

Ethics Declarations

Author Contribution

Data Availability

References

Additional Declarations

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