Verrucous carcinoma of the esophagus: improvement of diagnosis and prognosis

Satoshi Tabuchi¹, Kazuo Koyanagi²*, Soji Ozawa², Shigeyuki Kawachi¹

¹Department of Digestive and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center

²Department of Gastroenterological Surgery, Tokai University School of Medicine

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Abstract

Verrucous carcinoma of the esophagus (VCE) is a special variant form of esophageal squamous cell carcinoma. VCE presents a unique superficial growth pattern that is characterized as an exophytic, slow-growing mass. We reviewed previous reports of the 56 cases and divided them into two groups: from 1967 to 1999 (19 cases; the former period) and from 2000 to 2020 (37 cases; the latter period) to compare the diagnosis and prognosis of VCE. Patients with T4 disease tended to be higher in 6 (32%) of the19 cases in the former period. On the other hand, T1 and T2 diseases were high in 23 (62%) and T4 was very low; only 2 (5%) of the 37 cases in the latter period. It is presumed that surveillance by endoscopic examination has become common, as the risk factors and characteristic appearances of VCE are well known. Moreover, improvements in surgical procedures and perioperative management in recent years has been related to the favorable prognoses in the latter period. Since reports in the literature have stated that chemotherapy and radiotherapy might be inadequate as means of curative therapy, esophagectomy should be recommended as curative treatment because of VCE’s low potential for lymph node and distant organ metastasis.

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Introduction

Verrucous carcinoma of the esophagus (VCE) is a special variant form of esophageal squamous cell carcinoma. In 1967, Minielly et al. reported five cases of VCE for the first time¹. VCE is slow-growing, well-differentiated squamous cell malignancy associated with nodular, papillary, and wart-like appearance. VCE is often difficult to diagnose before surgical excision, because in most cases, the superficial layer of the tumor is covered by non-malignant tissue². Because of the paucity of cases, therapeutic strategies have not been well assessed. In this mini review we reviewed previous reports and discussed VCE.

Characteristics of verrucous carcinoma

We searched the literature that reported VCE using the keywords “esophagus” and “verrucous carcinoma” in the PubMed database during the period from 1967 to 2020 (Table 1). There were only 56 cases that has discussed VCE (including our case). Although males have predominated, the proportion of women has been higher in VCE patients (35 males, 19 females, 2 gender unknown) than that in conventional esophageal squamous cell carcinoma patients. Age has been as same as those of esophageal squamous cell carcinoma patients (median, 63 years; range, 36-79 years). Dysphagia was the most common chief complaint (47 (84%) of the 56 cases). The tumors have been predominantly located at the lower third of the esophagus (37 cases, 66%), and this frequent location in the lower-third of the esophagus has suggested that VCE might be associated with chronic inflammation of esophageal mucosa³.

Table 1: Reported cases of Verrucous carcinoma of the esophagus

No

Author

Year

Age/Sex

Location

1st diagnosis

Pre Tx.a diagnosis

Tumor size (cm)

Treatment

Prognosis

T

N

M

1

Minielly1

1967

58/M

upper

benign

VC (Bx.b 3 times)

9×8.5

OPEc

1m dead

3

0

0

2

1967

70/F

upper

VCd

VC

large tumor

RTe

N/Af

N/A

N/A

N/A

3

1967

70/F

upper

VC

VC

large tumor

RT

2m dead

4

N/A

N/A

4

1967

36/M

lower

SCCg

SCC

9×8

OPE

2m dead

4

＋

N/A

5

1967

57/M

lower

benign

VC (Bx. 2 times)

N/A

BSCh

5m dead

N/A

N/A

N/A

6

Parkinson13

1970

76/M

middle

SCC

SCC

7.5

BSC

1m dead

1b

0

0

7

Meyerowitz14

1971

45/M

lower

benign

benign

8×5.5

OPE, RT

9m dead

2

N/A

0

8

Sridher15

1980

54/M

lower

benign

benign

2

OPE

N/A

1b

0

N/A

9

Sakurai5

1983

78/M

upper

VC

VC

10×5

CTi

6m alive

4

N/A

N/A

10

Agha16

1984

66/M

upper

VC

VC

large tumor

BSC

2m dead

4

N/A

N/A

11

Barbier17

1987

50/F

lower

VC

VC

N/A

OPE

10m alive

1a

0

0

12

Koerfgen18

1988

75/M

lower

benign

SCC (Bx. repeatedly)

N/A

OPE

36m alive

2

0

0

13

1988

54/ unknown

lower

benign

SCC (Bx. repeatedly)

6.5×6.5

OPE

18m alive

2

0

0

14

Jasim2

1990

79/M

lower

benign

benign

9×6

BSC

dead

N/A

0

0

15

Biemond6

1991

76/F

middle

benign

benign

15

BSC

1m dead

4

0

0

16

Roach19

1993

67/M

upper

benign

VC (Bx. repeatedly)

7

BSC

2m dead

4

0

0

17

Garrard20

1994

51/F

middle

VC

VC

10

OPE

9m alive

2

0

0

18

Kavin3

1996

76/unknown

lower

benign

benign

N/A

BSC

1m dead

N/A

+

N/A

19

Malik21

1996

66/M

lower

benign

benign

5×2

OPE

36m alive

2

0

0

20

Tajiri22

2000

40/M

lower

VC

VC

0.6×0.8

EMRj

48m alive

1a

0

0

21

Ereno23

2001

65/F

middle

N/A

N/A

11

OPE

N/A

N/A

N/A

N/A

22

Osborn24

2003

67/M

lower

benign

benign

8×8

OPE

9m alive

2

0

0

23

Devlin7

2004

56/F

lower

benign

VC (Bx. 5 times)

2.7

OPE

14m alive

1b

0

0

24

Pfitzmann25

2004

66/F

lower

N/A

N/A

N/A

OPE

N/A

N/A

N/A

N/A

25

Liberale26

2005

41/M

lower

VC

VC

N/A

Antiviral Tx.

6m dead

4

N/A

N/A

26

Petris27

2005

73/M

lower

benign

benign

N/A

OPE

N/A

3

0

0

27

2005

58/M

lower

benign

benign

6×5.5

OPE

N/A

3

0

0

28

Na28

2009

50/M

middle

benign

VC (Bx. 5 times)

7.5×4.8

OPE

6m alive

2

0

0

29

Oh8

2009

73/F

upper

benign

VC (Bx. repeatedly)

3.5

BSC

23m alive

1a

0

0

30

Garcia29

2010

71/F

middle

benign

benign

3.9×2.5

OPE

N/A

2

0

0

31

Tonna30

2010

61/M

extensive

benign

benign

10

OPE

12m alive

1b

0

0

32

Munson31

2010

63/F

extensive

VC

VC

16

CRTk

N/A

3

＋

0

33

Taniyama32

2012

74/M

middle

benign

SCC (Bx. 3 times)

5

OPE

6m alive

2

0

0

34

Vieira33

2013

58/M

N/A

benign

benign

N/A

OPE

1m dead

2

0

0

35

Ahmed34

2013

58/F

middle-lower

VC

VC

N/A

OPE, CRT

N/A

N/A

N/A

N/A

36

Sweetser35

2014

61/M

extensive

N/A

N/A

N/A

OPE, CRT

72m alive

2

0

0

37

2014

73/F

lower

N/A

N/A

N/A

CRT

36m alive

N/A

N/A

N/A

38

2014

66/M

lower

N/A

N/A

N/A

OPE

120m alive

1

0

0

39

2014

70/F

extensive

N/A

N/A

N/A

OPE

6m dead

1

0

0

40

2014

71/M

middle

N/A

N/A

N/A

N/A

36m dead

2

0

0

41

2014

57/M

lower

N/A

N/A

N/A

N/A

N/A

3

0

0

42

2014

75/F

lower

N/A

N/A

N/A

N/A

N/A

1

0

0

43

2014

62/M

extensive

N/A

N/A

N/A

OPE

96m alive

3

0

0

44

2014

63/F

extensive

N/A

N/A

N/A

CRT

12m alive

3

0

0

45

2014

68/M

extensive

N/A

N/A

N/A

OPE, CRT

24m alive

1

0

0

46

2014

62/F

middle

N/A

N/A

N/A

OPE

24m alive

1

0

0

47

Behrens36

2014

77/M

extensive

benign

VC (Bx. 2 times)

9

EMR

84m alive

1a

0

0

48

Ramani37

2014

78/M

middle-lower

benign

VC (Bx. repeatedly)

5

CRT

N/A

4

+

0

49

Brandalise38

2015

64/M

extensive

benign

benign

16

OPE, RT

12m alive

3

0

0

50

Abe39

2016

68/M

lower

benign

benign

1

ESDl

N/A

1a

0

0

51

Egeland40

2016

67/M

lower

benign

benign

N/A

OPE

N/A

2

0

0

52

2016

59/M

N/A

benign

benign

N/A

OPE

N/A

2

0

0

53

Cox41

2017

62/M

middle

SCC

SCC

9.5

OPE

N/A

1b

0

0

54

Hoffmann42

2018

61/M

lower

VC

VC

N/A

OPE

24m alive

1b

0

0

55

2018

52/F

lower

VC

VC

10

OPE

24m alive

2

0

0

56

Tabuchi43

2020

56/F

lower

benign

SCC (Bx. 6 times)

12

OPE

96m alive

3

0

0

Tx.^a: Treatment; Bx.^b: Biopsy; OPE^c: Operation; VC^d: Verrucous carcinoma; RT^e: Irradiation; N/A^f: Not applicable; SCC^g: Squamous cell carcinoma; BSC^h: Best supportive care; CTⁱ: Chemotherapy; EMR^j: Endoscopic mucosal resection; CRT^k: Chemoradiation therapy; ESD^l: Endoscopic submucosal dissection

Although tumor sizes of VCE have been large, depth of invasion has been shallow. In 27 (82%) of the 33 cases in which tumor size was recorded, the tumor measured 5 cm or more in diameter. Tumor invasion has been limited to the muscle layer (T1: 16 cases and T2: 15cases): in 65% of the patients in which depth of tumor invasion was recorded, but in seventeen cases (35%) the tumor was locally advanced (T3: 9 cases and T4: 8 cases). In addition, lymph node metastasis (9%) and distant organ metastasis (0%) have occurred very low and these findings were considered as special features of VCE.

Treatment consisted of surgery in 34 cases, chemoradiation therapy in 7 cases, radiotherapy in 4 cases, chemotherapy in 1 case, and best supportive care in 8 cases. The effectiveness of both chemotherapeutic regimens and radiotherapy that was used to treat conventional squamous cell carcinoma has been very limited for VCE^4,5. If the surgery is technically possible to perform, esophageal resection should be considered even in a locally advanced VCE, because VCE has very low incidence of lymph node metastases and the limited sensitivity of chemotherapy and radiotherapy.

Comparison of diagnosis and prognosis of VCE according to the era

Histopathological diagnosis

We divided the literature reports into two groups: from 1967 to 1999 (19 cases; the former period) and from 2000 to 2020 (37 cases; the latter period), and compared the diagnosis and prognosis of VCE (Table.2). Despite the unique characteristic findings, it is difficult to make a definitive diagnosis of VCE because superficial biopsies tend to show only nonspecific acanthosis, parakeratosis, or hyperkeratosis, with associated acute and chronic inflammation. A deeper and full-thickness biopsy or a fully resected specimen is often needed to differentiate VCE from benign lesions^6,7. The histological picture of VCE and benign squamous cell papilloma is very similar. However, VCE tends to grow deeply and invasively, whereas benign squamous papilloma tends to grow superficially. Biemond et al.⁶ proposed that the histopathological findings of invasion were essential to differentiate VCE from benign squamous papilloma. It is very important to know that benign squamous papilloma sometimes shows no invasions, but dysplastic changes. In fact, only 15 (27%) of the 56 cases were diagnosed as esophageal VC or SCC based on the first biopsy pathology findings. In addition, 28 (50%) of the 56 cases were diagnosed as benign lesions by the first biopsy, and they were subjected to endoscopic biopsy many times in order to make a definitive diagnosis. However, in 16 (57%) of these 28cases, pre-treatment diagnosis were still benign lesions though repeated endoscopic biopsies, consequently diagnosis of malignancy could not be made before surgery or autopsy. The rates of accurate histopathological diagnosis have not changed between the two periods. Difficulty in the histopathological diagnosis from the biopsy specimen may be related to these lower accuracy rate, because differential diagnosis of VCE can usually be achieved by histological evaluation of surgically or endoscopically resected specimens⁸.

Table 2: Comparison of diagnosis and prognosis of VCE according to the era

	Former period (n=19) (1967-1999)	Latter period (n=37) (2000-2020)
1st diagnosis
Benign	11	17
VCa or SCCb	8	7
Unknown	0	13
Pre Tx.c diagnosis
Benign	6	10
VC or SCC	13	14
Unknown	0	13
T
1	3	13
2	5	10
3	1	8
4	6	2
Unknown	4	4
N
(−)	11	30
(＋)	2	2
Unknown	6	5
M
(−)	11	32
(＋)	0	0
Unknown	8	5
Treatment
OPEd	9	25
EMRe or ESDf	0	3
CRTg	0	4
RTh	2	0
CTi	1	0
Antiviral Tx.	0	1
BSCj	7	1
Unknown	0	3
Prognosis
Dead	11	4
Alive	6	19
Unknown	2	14

VC^a: Verrucous carcinoma; SCC^b: Squamous cell carcinoma; Tx.^c: Treatment; OPE^d: Operation; EMR^e: Endoscopic mucosal resection; ESD^f: Endoscopic submucosal dissection; CRT^g: Chemoradiation therapy; RT^h: Irradiation; CTⁱ: Chemotherapy; BSC^j: Best supportive care

Tumor staging

Regarding T factors, patients with T4 disease tended to be higher in 6 (32%) of the19 cases in the former period. On the other hand, T1 and T2 were high in 23 (62%) and T4 was very low; only 2 (5%) of the 37 cases in the latter period. Since the ability of histopathological diagnosis might be equal between the former period and the latter period, these differences in the depth of tumor invasion might be affected by improvement in diagnostic imaging equipment such as CT, MRI, and endoscopy. In addition to the classic risk factors such as heavy consumption of nicotine and alcohol, VCE is significantly associated with chronic inflammation of esophageal mucosa. Almost all patients had affected the medical histories that were typically associated with esophageal injury or chronic inflammation: achalasia, reflux esophagitis, candida esophagitis, and heavy consumption of nicotine and alcohol were found in 90% of the patients before the diagnosis of VCE³. Therefore, it is presumed that surveillance by endoscopic examination has become common that can detect the tumor in early stage, as the risk factors and characteristics appearances of the VCE are well known. Moreover, using EUS may provide information that is crucial to the diagnostic process⁷. Inflammatory histopathologic findings that extend deeper into the submucosa and the muscularis propria have been found in the majority of VCE. Since EUS enables to visualize the distorted architecture and local invasion of VCE, it is considered that EUS is ideally suited to detect these impressive changes in the esophageal wall and to establish the appropriate diagnosis of VCE.

Lymph node and distant metastases are known to be extremely rare. N factor did not change with time and lymph node metastasis tended to be less. Patient with positive lymph node metastasis was very low; in 2 (11%) of the19 cases in the former period and in 2 (5%) of the 37 cases in the latter period. There were no distant organ metastases in both the former period and the latter period. The reason why lymph node or distant metastasis is very limited is speculated that dysplasia of tumor cells is weak and alveolar nest formation is poor in the VCE tissues, as can be seen from the fact that it is difficult to distinguish it from a benign disease in pathological findings.

Treatment and prognosis

In the former period, treatment consisted of surgery in 9 cases (47%), radiotherapy in 2 cases (11%), chemotherapy in 1 case (5%), and best supportive care (BSC) in 7 cases (37%). On the other hands, in the latter period, treatment consisted of surgery in 25 cases (68%), endoscopic resection in 3 cases (8%), chemoradiation therapy in 4 cases (11%), antiviral treatment in 1 case (3%), and BSC in 1 case (3%). Among the documents that described the prognosis, 11(65%) of the 17 cases died in the former period, but only 4 (17%) of the 23 cases died in the latter period. In the former period, BSC was selected as a treatment in 7 (37%) of 19 cases, and tumor progression due to delay in diagnosis was suggested to be related to this high rate of immediate patient death. In the latter period, tumor resections including surgery and endoscopic resection were performed in the three quarters of patients. It is considered that these favorable prognoses in the latter period are due to the full understanding of the characteristics of VCE and the advancement in the imaging diagnosis, enabling early detection. Moreover, improvements in surgical procedures and perioperative management in recent years has been related to the favorable prognoses in the latter period as well as the low malignant potentials of VCE.

VCE patients uniformly respond well to surgical excision, if they are diagnosed before invasion of surrounding organs. Metastasis by VCE is exceptionally rare^9,10. The effectiveness of radiotherapy and chemotherapy has been very limited⁴. There has been only one report that could demonstrate the partial therapeutic response with bleomycin⁷. Gothals et al.⁹ and Kraus et al.¹⁰ have both demonstrated that radiation is ineffective. Radiotherapy appears to be associated with poor outcomes, because it tends to be followed by recurrence and early metastasis with anaplastic transformation. Therefore, chemoradiotherapy cannot become a treatment option for VCE.

Recent studies have suspected that human papillomavirus (HPV) infection may be involved in carcinogenesis of VCE¹¹. There are several reports of HPV-positive VCE cases¹². It could be proposed that antiviral treatment therapy might be a promising treatment for HPV-positive VCE and administration of HPV vaccine against VCE might prevent the acceleration of malignant progression.

Conclusions

The prognosis of VCE has improved recently, probably as the risk factors and characteristics appearances of the VCE have been well investigated. Esophagectomy should be recommended as curative treatment because of VCE’s low potential for metastasis and the limited effectiveness of chemotherapy and radiotherapy.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

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