Coexistence of esophageal verrucous carcinoma in situ and gastric intramucosal poorly differentiated adenocarcinoma: A case report

Abstract

BACKGROUND

This report describes an exceptionally rare case of coexisting esophageal verrucous carcinoma (EVC) in situ and gastric intramucosal poorly differentiated adenocarcinoma (GIPDA). EVC is a diagnostically challenging, well-differentiated squamous cell carcinoma that is often misdiagnosed on superficial biopsy. Documented cases of their co-occurrence are exceedingly rare. This report highlights this unusual dual pathology and underscores the critical role of deep endoscopic resection for the definitive diagnosis of EVC.

CASE SUMMARY

A 71-year-old man presented with a 3-month history of upper abdominal discomfort. Gastroscopy revealed concurrent esophageal and gastric lesions. Initial biopsies indicated esophageal papillary hyperplasia and GIPDA. The gastric adenocarcinoma was treated first with distal gastrectomy. On follow-up endoscopy ten months later, the esophageal lesion showed progression. Endoscopic submucosal dissection (ESD) was subsequently performed. The final pathological diagnosis of the completely excised esophageal lesion was verrucous carcinoma in situ, measuring 1.0 cm, with no submucosal invasion and clear margins. Immunohistochemical findings were consistent with verrucous carcinoma. The outcome was successful complete resection of both malignancies.

CONCLUSION

EVC, often missed by superficial biopsies, is addressed by ESD through securing a definitive diagnosis and achieving complete resection.

Key Words: Esophageal verrucous carcinoma; Gastric intramucosal poorly differentiated adenocarcinoma; Upper gastrointestinal cancer; Endoscopic submucosal dissection; Case report

Core Tip: This report presents an exceptionally rare case of coexisting esophageal verrucous carcinoma (EVC) in situ and gastric intramucosal poorly differentiated adenocarcinoma. It highlights the major diagnostic challenge posed by EVC, as superficial biopsies are frequently non-diagnostic and mimic benign conditions. The case underscores the critical role of endoscopic submucosal dissection (ESD), which served not only as a curative treatment but also as the definitive diagnostic procedure. By providing a full-thickness specimen, ESD ultimately confirmed the diagnosis and enabled a favorable prognosis through complete resection.

INTRODUCTION

Verrucous carcinoma, first reported in 1948, is a highly differentiated form of squamous cell carcinoma characterized by marked hyperkeratosis and white, raised lesions. It typically has a good prognosis and most commonly occurs in the head and neck, oral cavity, skin, genitalia, and cervix, with esophageal involvement being exceptionally rare[1].

Esophageal verrucous carcinoma (EVC) is an extremely rare variant of squamous cell carcinoma, notable for its distinct clinical behavior and diagnostic difficulty. It is typically a slow-growing, well-differentiated tumor with a propensity for local invasion but low rates of lymph node and distant metastasis[1]. Clinically, patients often present with dysphagia. Endoscopically, EVC appears as a white, warty, or cauliflower-like lesion, frequently mimicking candidal esophagitis. The principal diagnostic challenge lies in its histopathology; superficial biopsies often reveal only hyperkeratosis and inflammation, while the malignant cells reside in deeper layers[1]. This frequently leads to false-negative results, necessitating deep sampling or complete resection for a definitive diagnosis.

We present a case of coexisting gastric intramucosal poorly differentiated adenocarcinoma (GIPDA) and EVC in situ in a 71-year-old man. Through a review of the literature, we also summarize the clinical features and treatment methods for EVC.

CASE PRESENTATION

Chief complaints

A 71-year-old male farmer presented to our outpatient clinic on September 8, 2022, with a 3-month history of upper abdominal discomfort.

History of present illness

The patient reported a 3-month history of epigastric discomfort occurring after meals, which was relieved by activity. There was no abdominal pain, diarrhea, nausea, vomiting, dysphagia, chest tightness, or shortness of breath.

History of past illness

The patient had a 1-year history of hypertension, which was well controlled with oral nifedipine sustained-release tablets (20 mg bid).

Personal and family history

The patient denied any family history of gastrointestinal cancer.

Physical examination

Vital signs were as follows: Body temperature, 36.7 °C; blood pressure, 126/66 mmHg; heart rate, 78 beats per minute; respiratory rate, 18 breaths per minute. No jaundice was observed. The skin and sclera were anicteric. The abdomen was flat without visible venous collaterals or surgical scars. Bowel sounds were present at a rate of 5 per minute. The abdomen was tympanic to percussion, soft, and non-tender with no rebound tenderness. The liver and spleen were not palpable, and no abdominal masses were detected.

Laboratory examinations

No significantly abnormality was found in routine blood, urine, and feces analyses.

Imaging examinations

Initial gastroscopy (September 17, 2022) revealed a 0-Is lesion in the esophagus (31 cm from the incisors) and a Borrmann type II lesion measuring approximately 2.2 cm × 2.5 cm on the greater curvature of the lower stomach body. The gastric lesion was characterized by convergent rugae and an accompanying annular elevated margin, with an ulcerative lesion located at the center of the annular elevation. Magnifying endoscopy with narrow-band imaging (MENBI) revealed a positive demarcation line, loss of mucosal structure, and an irregular microvascular pattern (Figure 1). Biopsy pathology revealed: (1) An esophageal lesion showing papillary hyperplasia of the squamous epithelium with hyperkeratosis and parakeratosis (Figure 2A); and (2) A gastric lesion consistent with intramucosal poorly differentiated adenocarcinoma at the greater curvature of the lower gastric body (Figure 2B). Given that the biopsy of the esophageal lesion indicated benign pathology, no immediate intervention was undertaken, and regular endoscopic surveillance was advised. However, the gastric lesion presented as a Borrmann type II mass, measuring over 2 cm with surface ulceration. Biopsy pathological examination revealed an intramucosal poorly differentiated adenocarcinoma, which exceeded the criteria for endoscopic therapy. Following a detailed discussion with the patient and the family regarding the risks and benefits, a distal gastrectomy with D2 Lymphadenectomy and Billroth I reconstruction was performed on October 10, 2022. Surgical pathology of the gastrectomy specimen confirmed poorly differentiated adenocarcinoma in the mucosa, locally invading the submucosa, with massive lymphocyte hyperplasia in the stroma. No obvious perineural invasion, vascular tumor thrombus, or lymph node involvement was detected (Figure 2C).

Figure 1 Endoscopic manifestations of gastric and esophageal lesions. A: White-light endoscopy revealed a Borrmann type II lesion on the greater curvature of the lower stomach body, featuring an ulcer on the surface covered by a moss-like debris; B: Magnifying endoscopy with narrow-band imaging revealed a positive demarcation line, loss of mucosal structure, and an irregular microvascular pattern; C and D: Under white-light and narrow-band imaging, verrucous white patches with clear boundaries are visible; the biopsy specimen from these patches was soft.

Figure 2 Hematoxylin and eosin-stained histopathological features. A: The initial esophageal biopsy pathology showing papillary hyperplasia of the squamous epithelium with hyperkeratosis and parakeratosis 31 cm from the incisors; B: The gastric biopsy pathology [4 × hematoxylin and eosin (HE)] showing intramucosal poorly differentiated adenocarcinoma at the greater curvature of the lower gastric body; C: Pathological examination of a radical gastrectomy specimen (10 × HE) showing poorly differentiated adenocarcinoma at the greater curvature of the lower gastric body.

Follow-up gastroscopy (August 5, 2023) performed 10 months post-gastrectomy showed progression of the esophageal lesion at 31 cm. Narrow-band imaging with magnification revealed abnormal microvasculature and a blurred surface pattern, suggestive of early esophageal cancer. Consequently, ESD of the esophageal lesion was performed on September 22, 2023 (Figure 3). Pathology of ESD specimen revealed that the resected specimen (1.0 cm × 0.3 cm × 0.5 cm) showed carcinoma in situ with a verrucous architecture. All margins (basal and lateral) were negative, with no evidence of submucosal, lymphatic, vascular, or perineural invasion (Figure 4). Immunohistochemically, the lesion was positive for p63, p53, and D2-40 (basal cells), and the Ki-67 proliferation index was approximately 50% (Figure 5).

Figure 3 Endoscopic manifestations of the progressive esophageal lesion and the endoscopic submucosal dissection procedure. A: The lesion appears more protruded than before, showing a whitish and slightly yellowish appearance under white light; B: Narrow-band imaging revealed irregular blood vessels, while the surface structure remained indiscernible; C and D: Endoscopic submucosal dissection was performed to completely excise the lesion.

Figure 4 Histopathological features of the esophageal endoscopic submucosal dissection specimen (hematoxylin and eosin staining). A: Esophageal endoscopic submucosal dissection (ESD) specimen [4 × hematoxylin and eosin (HE)] showing an esophageal mass displaying carcinoma in situ (verrucous or papillary) with a stone pillar-like appearance 31 cm from the incisors; B: Esophageal ESD specimen (10 × HE) showing epithelial cell dysplasia, with no infiltration of the basal cells by the carcinoma in situ.

Figure 5 Immunohistochemical staining features of the esophageal endoscopic submucosal dissection specimen. A: D240 staining shows continuous linear positivity along the membranes of basal cells (clone number: D2–40, positivity was defined as brownish-yellow staining of the basal cell membrane); B: Ki67 staining shows a marked increase in positive cells in the basal layer, with an abnormal distribution pattern [clone number: 176B3C4, abnormal Ki-67 distribution in the squamous epithelium was defined by the presence of any of the following: (1) A higher number of positive cells in the basal layer (≥ 5/HPF); (2) No or significantly reduced expression of cells in the parabasal layer ( < 50%), or an equal or higher number of positive cells in the basal layer compared to the parabasal layer; and (3) The presence of Ki-67 expression in the epithelial superficial layer (> 2 cells/HPF)]; C: P53 staining shows diffuse strong nuclear expression (clone number: 882F5H1, positivity was defined as brownish-yellow staining of the squamous epithelial cell nucleus); D: P63 staining shows positive cytosolic nuclei in tumour cells (clone number: 281B6A9, positivity was defined as brownish-yellow staining of the squamous epithelial cell nucleus).

FINAL DIAGNOSIS

Combined with the patient’s medical history, the final diagnoses were: (1) GIPDA (post-resection); and (2) EVC in situ (completely resected via ESD).

TREATMENT

On October 10, 2022, the patient underwent distal gastrectomy with D2 Lymphadenectomy and Billroth I reconstruction for the gastric adenocarcinoma. Subsequently, on September 22, 2023, endoscopic submucosal dissection (ESD) was performed for complete excision of the progressive esophageal lesion.

OUTCOME AND FOLLOW-UP

The patient recovered well from both procedures. At the last follow-up on August 11, 2025, a surveillance endoscopy was performed, with no evidence of recurrence or metachronous lesions.

DISCUSSION

Diagnostic challenges of EVC

EVC is a rare variant of well-differentiated squamous cell carcinoma characterized by slow growth, favorable differentiation, and a low propensity for lymph node metastasis[1-6]. Genetically, EVC is notably defined by SMARCA4 mutations, whereas TP53 mutations and CDKN2A/B copy number variations are relatively infrequent[7-9].

The endoscopic features of early EVC primarily include: Flat lesions with scattered white speckles and the disappearance of the vascular network under white light; faint brownish areas accompanied by white papillary structures under NBI; and irregular papillary microsurface architecture with atypical B1-type intrapapillary capillary loops (IPCLs) under ME-NBI, findings that facilitate the diagnosis of early-stage carcinoma[10].

However, slow-growing EVC often presents diagnostic difficulties due to thick keratinization covering the tumor surface. Under white light, it manifests as a white, flat elevation with a coated appearance. The dense keratin layer frequently obscures the IPCLs under ME-NBI, significantly increasing the difficulty of diagnosis[5,11,12]. Consequently, superficial biopsies—which often only reveal fungal hyphae and mild cellular atypia—can lead to misdiagnosis as esophageal candidiasis or benign inflammation, resulting in pathological diagnostic delays[13]. As a result, most patients are diagnosed at an advanced stage, limiting the options for curative treatment and adversely affecting prognosis.

In summary, the definitive diagnosis of EVC should integrate characteristic endoscopic findings, histological features from full-thickness biopsies, and genetic testing results, rather than relying solely on superficial biopsy specimens.

Uniqueness of the present case

The uniqueness of this case is primarily manifested in two aspects. First, it represents a rare coexistence of double primary carcinomas. The patient was diagnosed with “esophageal verrucous carcinoma in situ” and “gastric poorly differentiated intramucosal adenocarcinoma”. While gastroesophageal double primary cancers are uncommon, the coexistence with the exceedingly rare EVC has been scantily documented in the literature. Second, the lesion exhibited an incidental detection pattern without symptoms of esophageal obstruction. Unlike the majority of cases reported in the literature where patients present with “dysphagia,” the chief complaint of this patient was merely “epigastric discomfort”. The esophageal lesion was discovered incidentally during gastroscopy performed for gastric symptoms, and the patient had not developed significant dysphagia even after gastric surgery. This atypical clinical presentation can likely be attributed to the small size of the EVC (1.0 cm) and its extremely indolent growth, which had not yet caused substantial luminal stenosis.

In summary, while this case aligns with the classic descriptions of EVC regarding endoscopic features, pathological morphology, and prognosis, its background as a “rare double primary cancer” and the “incidental discovery mode without obstructive symptoms” constitute a unique clinical scenario. This highlights the necessity for clinicians to remain vigilant for minute or early malignant esophageal lesions during gastroscopy in patients presenting with epigastric discomfort, particularly those with concurrent gastric lesions. Furthermore, when encountering multifocal gastroesophageal lesions, rare entities such as EVC should be included in the differential diagnosis.

Clinical practice implications

Clinicians should maintain a high index of suspicion for EVC when encountering chronic esophageal candidiasis refractory to antifungal therapy, or when endoscopic findings reveal verrucous, hyperkeratotic, or papillary lesions. However, prior to diagnosing EVC, a meticulous differential diagnosis must be performed to distinguish it from conditions such as esophageal papillomatosis, glycogenic acanthosis, and localized refractory fungal infections. Endoscopically, esophageal papillomatosis typically presents as spherical or hemispherical sessile protrusions with a characteristic central fibrovascular core within the papillae[14-16]. Glycogenic acanthosis is predominantly characterized by well-demarcated white plaques[17]. Additionally, localized refractory fungal infections should be considered, particularly in high-risk populations such as the elderly, debilitated individuals, or immunocompromised hosts[18].

The diagnostic and therapeutic workflow for EVC may follow these steps: First, deep biopsies should be obtained for suspicious lesions to secure adequate tissue for diagnosis based on characteristic histopathological and endoscopic features. Once EVC is confirmed, staging assessments using endoscopic ultrasound, computed tomography (CT), and positron emission tomography-CT are recommended to evaluate the depth of invasion (T stage) and the presence of nodal or distant metastasis (N/M stages). Finally, given its rarity, there is currently no universally established standardized protocol. Treatment decisions should be individualized through a multidisciplinary team discussion involving experts from endoscopy, esophageal surgery, oncology, radiology, and pathology to optimize patient outcomes[13].

Based on current literature, the selection of treatment modalities for EVC should be strictly contingent upon tumor stage and extent, as shown in Table 1[19-43]. For early-stage, localized EVC confined to the mucosa (stage T1) without evidence of lymph node or distant metastasis, endoscopic resection—specifically ESD—is the preferred approach[19]. ESD not only provides an en bloc specimen for definitive pathological confirmation but also achieves radical cure in a single session. Therefore, early diagnosis followed by ESD is paramount for ensuring a favorable prognosis in EVC patients[2,11,20-23]. For locally advanced cases or those unsuitable for ESD—such as tumors with circumferential growth or advanced local disease (T3/T4 stages)—surgical resection is recommended[1,5,24-26]. Although EVC is generally less sensitive to chemoradiation, these modalities can be employed as neoadjuvant or concurrent therapies to downsize the tumor, facilitating surgical resection. Common regimens include FP (5-FU + cisplatin) with radiotherapy and PC (paclitaxel + carboplatin) with radiotherapy[27-29]. When the disease progresses to an advanced stage (with distant metastasis) or when the patient is unfit for aggressive therapy, the focus shifts to palliative care aimed at alleviating symptoms and improving quality of life[13].

Table 1 Summary of clinicopathological features of previously reported cases of esophageal verrucous carcinoma.

Number	Patient demographics	Presenting symptoms	Tumor location	Initial biopsy findings	Definitive diagnostic method	Treatment approach	Clinical outcomes	Ref.
1	A 76-year-old Caucasian man	Hematemesis	Middle esophagus	Well-differentiated squamous carcinoma	Autopsy	Supportive treatment	The patient developed bilateral bronchopneumonia after admission and died suddenly on day 9	[30]
2	A 78-year-old Japanese woman	Progressive dysphagia	Upper esophagus	Hyperkeratosis and swollen rete peg of well-differentiated squamous cells	Pathological examination of the endoscopic biopsy	Intravenous injection of bleomycin for chemotherapy, with a total dose of 150 mg	The patient’s symptoms significantly resolved within 3 weeks of medication; esophageal angiography at 2 months showed tumor shrinkage; at 6 months after drug discontinuation, the patient remained asymptomatic and in good general condition	[31]
3	A 60-year-old woman	Progressive dysphagia and digestive hemorrhage	Middle and distal esophagus	Epithelial proliferation with lengthened papillae, hyperkeratosis, hyperacanthosis, and severe dysplasia		Subtotal esophagectomy		[32]
4	A 79-year-old man	Dysphagia and weight loss	Distal esophagus	Keratinized well-differentiated squamous cell	Autopsy		The patient deteriorated rapidly and died	[33]
5	A 66-year-old white man	Progressive dysphagia	Distal esophagus	Focal dysplasia	Pathological examination of the surgical specimen	Esophagectomy	The patient has shown no evidence of tumor recurrence 22 months after resection	[34]
6	A 65-year-old woman	Dysphagia	Middle esophagus	Non-branching, filiform papillae with a thick layer of parakeratosis	Pathological examination of the surgical specimen	Esophagogastrectomy		[35]
7	A 56-year-old woman		Distal esophagus	Inflammation	Pathological examination of the endoscopic biopsy	Esophagectomy	The patient has shown no evidence of progression	[36]
8	A 41-year-old man	Persistent atypical thoracic pain	Distal esophagus	Active mucosal mycosis, multiple ulcerations	Pathological examination of the endoscopic biopsy	Local antiviral treatment with hydroxy-phosphonyl-methoxypropyl-cytosine 5 mg/kg a week	The patient ultimately died 6 months after referral to the author’s center	[37]
9	A 63-year-old woman	Dysphagia, cough, and chest pain	Upper and middle esophagus	Well-differentiated squamous cell carcinoma	Endoscopic ultrasound and pathological examination of the EUS-guided biopsies	Chemoradiation		[38]
10	A 71-year-old woman	Progressive dysphagia, retrosternal pain, and hematemesis	Middle esophagus	Inflammation	Pathological examination of the surgical specimen	Esophagogastrectomy		[39]
11	A 61-year-old man	Chest pain, dysphagia, and odynophagia	Distal esophagus	Hyperkeratosis with intraepithelial neutrophils and eosinophils	Pathological examination of the surgical specimen	Esophagectomy with gastric pull-up		[22]
12	A 58-year-old woman	Dysphagia	Middle and distal esophagus	Pseudoepitheliomatous hyperplasia	Endoscopic ultrasound and pathological examination of the surgical specimen	Preoperative chemoradiation and esophagectomy		[40]
13	A 78-year-old African American man	Dysphagia and weight loss	Middle and distal esophagus	Squamous epithelial cells with parakeratosis, inflammation, and ulceration, and focal squamous cell with atypia	Pathological examination of the endoscopic extensive biopsies	Esophageal stenting and chemoradiation		[23]
14	A 64-year-old man	Progressive dysphagia and weight loss	Middle esophagus	Squamous epithelium with candida	Pathological examination of the surgical specimen	Endoscopic esophagectomy, lymphadenectomy, ablation with argon plasma, and adjuvant radiotherapy	The patient is doing well with no signs of disease at 12-month follow-up	[6]
15	A 68-year-old Asian man	Regular health check	Distal esophagus	Squamous high-grade intraepithelial neoplasia	Pathological examination of the resected esophageal specimen	Endoscopic submucosal dissection		[41]
16	A 51-year-old man	Dysphagia and rumination	Distal esophagus	Squamous epithelium with candida	Pathological examination of the resected esophageal specimen	Endoscopic submucosal dissection		[42]
17	A 61-year-old man	Dysphagia	Distal esophagus	Well-differentiated squamo-proliferative process with low-grade cytological atypia	Pathological examination of the surgical specimen	Esophagectomy	The patient developed an anastomotic stricture requiring several dilatations but is otherwise well 24 months later	[43]
18	A 52-year-old woman	Dysphagia	Distal esophagus	Inflammation and hyperkeratosis	Pathological examination of the surgical specimen	Esophagectomy	The patient had mild postoperative pain but is otherwise well 24 months post-procedure	[43]
19	A 67-year-old woman	Progressive dysphagia and weight loss	Middle esophagus	Squamous hyperplasia with parakeratosis	Pathological examination of endoscopic mucosal resection specimens	Chemoradiation		[26]
20	A 50-year-old man	Progressive dysphagia and weight loss	Middle esophagus	Papillomatous and verruciform keratinizing hyperplasia	Pathological examination of the surgical specimen	Esophagectomy with tubular gastroplasty	The patient developed cervical anastomotic leakage and secondary respiratory distress after the operation	[5]
21	A 65-year-old man	Progressive dysphagia	Gastro-oesophageal junction	Squamous hyperplasia	Pathological examination of endoscopic mucosal resection specimens	Endoscopic mucosa resection	The patient continues annual surveillance endoscopy, with the latest showing no residual lesion	[19]
22	A 64-year-old man	Dysphagia and sore throat	Middle esophagus	Reactive hyperkeratosis of the squamous epithelium with minimal atypia	Pathological examination of endoscopic mucosal resection specimens	Endoscopic mucosa resection		[2]
23	A 56-year-old woman	Dysphagia	Distal esophagus	Polypoid lesions and fungal infection	Pathological examination of the surgical specimen	Esophagectomy with lymph node dissection	The patient has shown no signs of recurrence in the 8 years since surgery	[1]
24	A 53-year-old woman	Regular health check	Middle esophagus	Superficial epithelial differentiation with evident cellular atypia	Pathological examination of the resected esophageal specimen	Endoscopic submucosal dissection		[11]
25	A 60-year-old Japanese man	Regular health check	Adjacent to the Barrett’s esophagus lesion	Cell proliferation of the squamous epithelium	Pathological examination of the resected esophageal specimen	Endoscopic submucosal dissection	The patient was closely monitored and showed no recurrence at 3 months after endoscopic submucosal dissection	[12]
26	A 54-year-old man	Swallowing dysfunction	Middle esophagus	Early esophageal cancer	Pathological examination of the resected esophageal specimen	Endoscopic submucosal dissection		[10]

CONCLUSION

This report highlights an exceptionally rare case of coexisting EVC in situ and GIPDA, offering several important insights for clinical practice. First, it underscores that coexisting upper gastrointestinal malignancies, though rare, can occur. The incidental discovery of an asymptomatic early esophageal cancer during work-up for gastric symptoms reinforces the value of thorough endoscopic examination. Second, it reaffirms the significant diagnostic challenge of EVC. Superficial biopsies are frequently non-diagnostic, as seen in our case where only hyperkeratosis was initially found. This necessitates a high index of suspicion and underscores the role of close endoscopic surveillance or diagnostic excision (e.g., ESD) for persistent or progressive lesions. Finally, ESD served a dual purpose here: Providing the definitive diagnosis via complete specimen evaluation and achieving curative treatment.

ACKNOWLEDGEMENTS

We would like to thank all individuals who contributed to the development and revision of this literature review. Special thanks go to those who provided valuable insights and assistance during the revision process.