Esophageal papillomatosis: an exceedingly rare disease

EPS may result from chronic mucosal irritation which is induced by chemical and mechanical mucosal injuries. Gastroesophageal reflux is the most popular chemical factor that is associated with an underlying esophageal inflammatory process. In animal model studies, gastroesophageal and duodenal reflux have been confirmed to induce EPS [11‐13]. Among the EPS cases, more than a quarter of patients had a prolonged chronic reflux disease and repeated heartburn. Chemical induction experiments were also performed using the carcinogen, diethylnitrosamine (DEN) [13] and EPS was detected in approximatively 50% of the rats that were fed with DEN alone and this proportion increased to 61.1% when associated with gastroesophageal reflux. Progressive hyperplasia of the papillae and epithelium led to the formation of papillomas. Other chemical factors, such as tobacco and alcohol abuse are also considered as a lifetime risk of EP [10, 14], which can also be found in EPS cases.

Some reports suggested that mechanical injuries, such as previous and repeated esophageal dilatations, a prolonged nasogastric intubation, and metal stent, were associated with the occurrence of EP [10]. It can also been seen in EPS cases [15‐17]. For instance, a 78-year-old man with distal esophagus stricture, who had to undergo repeated esophageal dilatations every 6–8 weeks and for more than 4 years, was diagnosed with EPS [16]. Another example was reported by Karras [17] who described the first EPS case following a 6-week placement of a self-expanding metal stent in a patient.

All the above conditions support the hypothesis that mucosal injury and regeneration underlie the etiology of EPS formation. A cellular damage-repair response, induced by prolonged chemical and mechanical mucosal irritations could contribute to an hyperregeneration process, associated with EPS development.

HPV is now considered to be closely related to EP and esophageal cancer and was suggested as one of the etiological factors [18, 19]. HPV is a non-enveloped double-stranded DNA virus (> 8 kb), that replicates in the nucleus of infected host cells. Until now, more than 100 HPV genotypes have been identified and the ratio of HPV positive EP ranges from 10.5 to 21.3% [10, 20]. In the reports of 53 EPS cases, 29 cases underwent HPV detection, 37.9% (11/29) detected HPV in these patients (Table 1). HPV testing methods vary from immunohistochemistry (IHC), dot blot hybridization (DB), in situ hybridization (ISH), polymerase chain reaction (PCR) to transmission electron microscopy (TEM). Some researchers suggested that PCR method should be used to test for HPV DNA due to its high sensitivity [10, 29]; however, others thought that even with more sensitive molecular analysis techniques, HPV DNA is not consistently recovered from the lesions [30, 31]. Thus, the true incidence of HPV infection may be underestimated, and the main reason may be due to the currently available HPV testing methods that only detect the most common viral subtypes.

In 11 HPV positive cases, 12 virus types were detected (Table 1) and approximatively half of these (6/11) harbored HPV types 6 and/or 11. It is well known that the vast majority of recurrent respiratory papillomatosis (RRP) lesions are caused by the above 2 types [32]. It's worth mentioning that 4 of these were associated with respiratory papillomas, with an average age not exceeding 7.8-year-old [7, 23, 24]. We can speculate that to some extent, EPS can co-exist with the respiratory system papillomas when HPV positive. HPV can be grouped as high or low risk according to their contribution to malignant changes. HPV types 6 and 11 belongs to the low-risk type that may induce benign tumors. According to the reports, 4 cases (4/11) involved HPV type 16, which is considered as a high-risk type that is strongly associated with malignancies. And half of the cases suffered from esophageal cancer [15, 26]. When a high-risk type HPV is detected, we need to be aware of malignant tumors.

Although HPV plays an important role in the occurrence of EPS, it is not yet clear how patients get infected. Morris [33] proposed that when newborns passage through an HPV infected canal, the transmission may occur in the upper respiratory/digestive tracts by contamination. In the EPS reports, delivery [6], sexual [29], and direct contact transmission [24] may facilitate HPV implantation.

In addition to chronic mucosal irritation and HPV infection, genetic factors are also involved in EPS pathogenesis. Among the 53 cases, 6 Focal dermal hypoplasia (FDH), also been called Goltz syndrome, were reported to manifest with EPS (Table 2). Goltz syndrome is a rare multisystem disorder that is characterized by cutaneous, skeletal, dental, ocular, and soft-tissue defects. Researchers suppose that Goltz syndrome is caused by genetic mutations in the PORCN gene [40, 41] that is associated with a X-linked dominant condition, characteristic of female genetic predominance. The 6 cases were all females aged between 3 and 56 years old. Two of them were proved to carry a PORCH gene mutation. Nasr [38] proposed that EPS could be the gastrointestinal phenotypic manifestation of Goltz syndrome. In a four-generation family with angioma serpiginosum (AS), among the six female patients, two sisters of the third generation had EPS [42]. AS is a congenital nevoid disorder, characterized by pinpoint violaceous to coppery red punctuates on an erythematous base. Both autosomal and X-linked dominant inheritances have been considered. In this family, an X-linked dominant condition mapping to Xp11.3-Xq12 was confirmed. In conclusion, genetic mutations may be related to EPS development.

From the series of EPS cases, we cannot rule out the possibility that EPS may be caused by the cooperation of multiple factors.

In contrast to the clinical limitations associated with the isolated papilloma, EPS shows several clinical symptoms. Dysphagia is the first observed symptom and constitutes the most typical manifestation of this condition. Over half of the EPS patients (32/53) bore this pain regardless of age that ranges from 2 to 84 years old [24, 43]. Heartburn is less common than dysphagia and some patients have been diagnosed as gastroesophageal reflux disease (GERD) or chronic reflux disease. Other symptoms, such as epigastric abdominal discomfort and dyspepsia, were occasionally reported. Other patients also presented with respiratory symptoms when associated with respiratory papillomatosis, such as noisy breathing, stridor and aphonia [6, 7, 23, 24, 44]. More than one in six patients lost weight and some asymptomatic patients were accidentally discovered [8, 45‐48].

Although some cases were first identified by esophagogram, which showed the presence of multiple filling defects, the diagnosis of EPS has to rely on esophagogastroduodenoscopy (EGD). The lesions usually appear as small, white or pink colored, with a smooth or slightly rough surface, sessile or pedunculated forms and with a close-set pattern (Fig. 1) [47]. Because of the extending growth pattern, papillomas are uncountable. It can grow as limited or widespread and with variable sizes, ranging from 1 to 15 mm [7, 49]. A total of 21 cases showed that the papillomatosis spread throughout the whole esophagus. Others range from 2 to 12 cm and most of the lesions covered the middle and/or distal esophagus. In addition, varying degrees of esophageal strictures can be found. It is noteworthy to point out that all lesions of the Goltz syndrome with EPS, involved the distal esophagus (Table 2). Special endoscopy technologies were also used to detect and distinguish EPS lesions, such as narrow band imaging (NBI) with magnifying endoscopy [45, 47, 50], and Lugol’s solution staining [14, 51] and endoscopic ultrasonography [39, 52, 53].

EP was classified as an esophageal benign epithelial tumor and its association with cancer is extremely rare [54, 55]. Although only a handful of EPS cases were disclosed, 12 cases were reported to be complicated with esophageal cancer, accounting for approximatively 22.6% of all cases (Table 3). There are no differences between female and male cases and half of the lesions were in the middle esophagus. The pathology suggested the presence of an esophageal squamous cell carcinoma (ESCC), which development is frequently noted in HPV associated diseases. However, only 2 cases, that had an HPV infection, were confirmed (Table 2). It seems that in this situation, HPV is not the main factor inducing ESCC. Additionally, high-grade dysplasia can be detected in the EPS tissue [16, 28, 60]. Interestingly, some patients acquired EPS, 1–3 year after esophageal carcinoma esophagectomy and gastric carcinoma surgery [17, 49, 58, 61], in which gastroesophageal reflux may play an important role during the process. Other EPS cases can also be found to be associated with oropharyngeal cancer and gastric adenocarcinoma [27, 62, 63], for which there are no suitable explanations. Thus, the cause of the malignant transformation is unclear and controversial; however, the malignant potential of EPS cannot be ignored.

The diagnosis of EPS with ESCC is extremely difficult and time-consuming due to the extensive and numerous lesions. To ensure a better results’ accuracy, some patients had to undergo multiple biopsies (from 2 to 15 times) and endoscopic mucosal resection (EMR) [52, 53, 56, 57]. Moreover, it took the clinicians 3–9 years to establish a diagnosis, and in some cases, the confirmation required esophagectomy [53, 56, 57]. Therefore, when EPS is disclosed, accurate and repeated biopsies are necessary.

From the reports, 13 of the 53 cases were complicated with extraesophageal papillomas (Table 4). Interestingly, 84.62% (11/13) of the lesions were located at the respiratory tract. Mucocutaneous papillomas are a common finding of the Goltz syndrome, and EPS is a rare manifestation (Table 2). This also happens with acanthosis nigricans (AN) [45], a condition, characterized by a dark pigmented thickening of the skin, with hyperkeratosis and papillomatosis and a basal layer hyperpigmentation. Patients with RRP can also associate with EPS, which is HPV induced. Therefore, we should pay more attention to patients with respiratory papillomas, whether affected with Goltz syndrome and AN, or with HPV infection.

To improve the symptoms of gastroesophageal reflux, anti-reflux medications, such as proton pump inhibitors (PPI) are commonly used. Since HPV infection was suggested as one of the EPS causes, etiological treatments were therefore, administered. For instance, a 3.5-month-old boy suffering from EPS and RRP, with HPV type 6 and 11 infections, underwent a total of 11 repeated microlaryngoscopic surgeries and laser photocoagulation. Unfortunately, the treatment effects were poor and resulted in a repeated recurrence [7]. When he was 2 1/2-year-old, he was treated with a 4-valent HPV vaccine and after three doses, both laryngeal and esophageal lesions completely disappeared and no papillomas were detected after 2 years follow-up. Interferon alpha can also be used to treat the disease based on its antiviral effects [25, 26]. However, it seems that it did not work well during the process. It is worth mentioning that a case of treatment with (S)-l-(3-hydroxy-2-phosphonylmethoxypropy1) cytosine (HPMPC) was successful [26]. The patient suffered recurrent EPS attacks for approximatively 6 years and during that period, she unsuccessfully received various treatments, including esophagectomy, Nd–YAG laser photocoagulation and interferon alpha injection, until HPMPC was introduced. Local injections of HPMPC were performed 10 times during the 7 months following the lesions’ gradual regression. The reporter speculated that one of the potential mechanisms was the inhibitory effect of the HPMPC diphosphate on the viral DNA polymerization process.

Various endoscopic treatments were used to manage the EPS lesions, including argon plasma coagulation (APC), Nd-YAG laser, radiofrequency ablation, cryotherapy and photodynamic therapy (PDT). The first three types induce rapid coagulative necrosis in EPS tissues through the heating effect. Although part of the effects was temporary, they were confirmed to be helpful in clearing away the lesions [25, 26, 36, 37, 58, 65]. Cryotherapy with spray of liquid nitrogen cryogen under endoscopy was successfully introduced to remove EPS [62, 66], which led lesions’ degeneration and necrosis. Additionally, Wolfsen et al. [43] were the first to introduce PDT to the therapy of EPS and provided a successful example. Porfimer sodium was used as photosensitizer that generates reactive oxygen and induced mucosal necrosis following laser radiation. Furthermore, EMR can be used when the lesion is limited [58, 67] and no previous studies attempted resecting the lesion by endoscopic submucosal dissection (ESD). Perhaps ESD is another viable option since it can remove a wide range of mucosa. Although the above treatments raised hopes, some studies considered that endoscopic therapy was not amenable for this condition [50, 53] due to the extensiveness of the lesions. Despite the effectiveness of these treatments in the short term, endoscopists always felt helpless against EPS repeated recurrence. In addition, to improve the esophageal stricture, repeated dilatations, and metal stent placements, were also adopted [14‐16, 43, 52].

Esophagectomy is the most ideal way to eliminate EPS with ESCC [15, 26, 39, 53, 56‐58] and this treatment was also used to treat patients with severe dysplasia [28, 60]. The surgical options vary from subtotal to total esophagectomy. Most lesions were removed by operation despite some small, remaining, and recurrent papillomatosis in the residual esophagus and the anastomotic site, which can be cleared away by endoscopic management. However, the choice of surgery is still prudent due to the cases that are mostly benign.

Among the 30 cases that received the above treatments, only 9 (30%) had been reported to be recurrence free during the 3 months to 2 years follow-up. Raising an optimal management is extremely difficult for clinicians since no guidelines can be followed. Except for esophagectomy, the medicine and endoscopic treatments are shown in Table 5.