Adenocarcinoma of the duodenal papilla with synchronous peritoneal metastases-5 years of overall survival: A case report

Abstract

BACKGROUND

Ampullary adenocarcinomas are a rare disease. They can be classified anatomically or according to their histology into intestinal, pancreatobiliary, and mixed subtypes, with different subtypes having distinct prognoses and potential treatments. We report a clinical case of a patient with mixed type adenocarcinoma of the ampulla of Vater, with predominantly intestinal histology, associated with an isolated and synchronous peritoneal carcinomatosis. It is the only case reported in the literature of duodenal ampulla cancer with synchronous peritoneal metastases, with long-term survival.

CASE SUMMARY

A 53-year-old male patient with non-insulin-dependent diabetes presented with acute abdominal pain in the right hypochondrium. Images revealed dilatation of the biliary tract and the duct of Wirsung, without a clear obstructive factor. Upper gastrointestinal endoscopy revealed a tumor in the duodenal papilla. Biopsies confirmed an adenocarcinoma. In the first surgical step, a biliodigestive bypass was performed in association with resection of the carcinomatosis. Peritoneal metastases was found during the intraoperative period. Subsequently, chemotherapy with the folinic acid, fluorouracil, and oxaliplatin regimen was administered based on histology, and a favorable response was achieved. After a multidisciplinary discussion, the Whipple procedure was performed. A delayed biopsy showed disease-free margins. The patient achieved 5 years of overall survival in August 2024, and 4 years of disease-free survival in September 2024.

CONCLUSION

We conclude that an important value of this work is showing individualized treatment for a patient with cancer.

Key Words: Ampullary adenocarcinoma; Ampulla of Vater; Duodenal tumor; Carcinomatosis; Peritoneal metastases; Case report

Core Tip: Ampullary adenocarcinomas are a rare disease. We present a patient with intestinal ampulla adenocarcinoma subtype with synchronic peritoneal metastases resected, and a subsequent favorable response to chemotherapy. He underwent surgery, achieving R0 resection and long-term disease-free survival. Resection of the peritoneal lesion, without the addition of concomitant hyperthermic intraperitoneal chemotherapy, is in accordance with the last evidence about this topic in digestive tumors. Therefore, we do not suggest initially classifying these cases as out of therapeutic reach.

INTRODUCTION

Ampullary adenocarcinomas are a rare disease, comprising only 0.2% of gastrointestinal cancers[1,2]. The ampulla of Vater is composed of three anatomical components: The ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct. Ampullary adenocarcinomas can be classified according to the anatomic location within the ampulla of Vater as well as their histologic features[3-6].

From an anatomic point of view, tumors of the ampulla of Vater can arise from different locations. One possibility is that a tumor can appear in the ampulla (intra-ampullary), arising from an intra-ampullary papillary tubular neoplasm, or as an ampullary ductal (pancreaticobiliary type). The second possibility is that a tumor could be periampullary/ampullary duodenal (arising from the duodenal surface of the papilla). Finally, it could be a mixed type. The first possibility, from a duodenum intraluminal view, appears as a subtle ulcer, mucosa-covered elevations, or protruding granular material. The second tumor possibility often grows from an adenoma, characteristically as an ulcerating or vegetating mass[3-6].

It is possible to precisely determine three differential diagnoses of ampullary adenocarcinoma: Carcinoma of the distal common bile duct, carcinoma of the main pancreatic duct, and duodenal tumors of the second segment (other than periampullary or ampullary adenocarcinoma), as these cancers can originate in different, although closely located, anatomical regions within the gastrointestinal tract. These differential diagnoses are strictly linked to subtypes of adenocarcinoma of ampulla of Vater. Periampullary/ampullary duodenal tumors that arise from the duodenal epithelium are histologically very similar, but not identical to other duodenal tumors, and they are also similar to colon cancer. On the other hand, intra-ampullary ductal tumors are resembling to distal common bile duct carcinoma and/or main pancreatic duct carcinoma, depending on their epithelial origin. Regarding other differential diagnoses, it is possible to diagnose adenocarcinoma of ampulla of Vater in its early stages and confirm that the cancer originates from the ampulla. However, it is very difficult to differentiate them when the tumors compromise multiple structures. Thus, the possibility of establishing a differential diagnosis depends mainly on the ability to anatomically locate the tumor[3-6].

From a histological point of view, most ampullary adenocarcinomas are gland-forming (tubular) and classically divided into intestinal, pancreatobiliary, and mixed types, with the last group constituting 40% of cases. It is important to consider the physiopathology of these tumors and note that the ampulla is a transition region between the intestinal epithelium of the duodenum and the pancreatobiliary epithelium from the pancreatic and biliary ducts, and with different etiopathogenic factors. It is a variation zone, where the intestinal epithelium in this location is similar but not identical to the colon. A comparable phenomenon occurs with the ampullary pancreatobiliary epithelium, which is not exactly like that of the pancreatobiliary ducts[4].

In addition to the abovementioned tumor types, there are other non-glandular patterns of carcinoma that can be isolated or mixed. The followings patterns have been described: Mucinous adenocarcinoma, medullary carcinoma, poorly cohesive carcinoma (signet ring cell), adenosquamous carcinoma, invasive papillary adenocarcinoma, neuroendocrine carcinoma, and undifferentiated carcinoma[4,5].

The use of immunohistochemistry is widely used for the adequate characterization of these tumors. Tumors of the intestinal type express high levels of the biomarkers cytokeratin 20 (CK20), caudal-related homeobox transcription factor 2 (CDX2), and mucin 2 (MUC2), regardless of mucin 1 (MUC1) expression level, also known as epithelial membrane antigen. Tumors of the pancreatobiliary type are positive for MUC1 and negative for CDX2 and MUC2, regardless of CK20 expression level, and may also highly express cytokeratin 7 (CK7) and mucin 5AC (MUC5AC)[1,5]. It is also described in literature that a high expression of carbohydrate antigen 19-9 (CA19-9), MUC1, and mucin 6 (MUC6) demonstrate biliopancreatic differentiation, while MUC5AC and CK7 markers can be seen in both histological types[4,6].

This histological differentiation has prognostic and therapeutic implications. Tumors with intestinal histology have a better prognosis than other histological types and a favorable response to chemotherapy regimens against colon cancer. On the other hand, tumors classified histologically as pancreaticobiliary have a worse prognosis than other cancer types in the same region and may show a better response to therapies against cancers of the biliary tract and pancreas[1,2,3,7].

We present a clinical case of an adenocarcinoma of the ampulla of Vater with intestinal predominance, associated with a synchronous peritoneal carcinomatosis. It is the only case reported in the literature of duodenal ampulla cancer with synchronous peritoneal metastases, with long-term survival.

CASE PRESENTATION

Chief complaints

A 53-year-old male patient with non-insulin-dependent diabetes presented with acute abdominal pain in the right hypochondrium in August 2019.

History of present illness

The patient was afebrile, with no nausea or weight loss.

History of past illness

The patient had no history of past illnesses.

Personal and family history

The patient had no personal or family history of cancer.

Physical examination

Physical examination revealed mild pain in the right hypochondrium. The patient did not present jaundice.

Laboratory examinations

Laboratory tests showed alterations of liver enzymes including alkaline phosphatase (218 U/L), gamma-glutamyl transferase (687 U/L), total bilirubin (0.55 mg/dL), and direct bilirubin (0.23 mg/dL). In addition, elevated white blood cells (leukocytosis) of 14100 μL was found.

Imaging examinations

Computed tomography (CT) scan with intravenous contrast, and magnetic resonance imaging with contrast plus magnetic resonance cholangiopancreatography, were performed. These images revealed dilatation of the biliary tract and the duct of Wirsung, without a clear obstructive factor.

Based on the above findings, upper gastrointestinal endoscopy (UGE) was realized and revealed a tumoral lesion in the duodenal papilla. Biopsies confirmed an adenocarcinoma. Subsequently, an endoscopic ultrasound was made, which revealed a 15 mm lesion. The imaging test showed no evidence of tumor infiltration to the common bile duct or pancreas, and also did not show choledocholithiasis. Two regional lymph nodes were observed, of which the largest was 9 mm.

FINAL DIAGNOSIS

Biopsies revealed a moderately differentiated tubular adenocarcinoma. Immunohistochemistry showed expression of the following biomarkers: High CDX2 expression in the nuclei of neoplastic cells (NCs), CA19-9 expression in isolated NCs, MUC1 and MUC5AC expression in a proportion of NCs, and MUC6 expression in isolated cells. Additional staining showed intense CK20 and less intense CK7 labeling. The findings revealed a mixed type of duodenal papillary adenocarcinoma, with intestinal predominance (Figure 1).

Figure 1 Ampullary adenocarcinoma. A: Endoscopic image at diagnosis (courtesy of Dr. Carlos León); B: Macroscopic image of surgical specimen after adjuvant treatment.

TREATMENT

The Whipple procedure was programmed in December 2019. During the procedure itself, a lesion of 5 mm was found and resected in the mesentery. The intraoperative biopsy result was positive for adenocarcinoma in the peritoneum. Therefore, instead of the planned surgery, Roux-en-Y choledochojejunostomy anastomosis and a cholecystectomy were performed. Subsequently, the patient received 12 cycles of the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen, which were administered between January and July 2020. Control examinations consisted of CT scans and UGE. Treatment led to a decrease in tumor size with no detectable distant lesions. In September 2020, the patient underwent a new surgical intervention. During the procedure, localized disease was observed without peritoneal implants, so a pancreatoduodenectomy was achieved. The gastrointestinal transit was reconstructed with a pancreato-gastro anastomosis, with a new choledochojejunostomy anastomosis. The previous Roux-en-Y was respected, and a gastro-jejunum anastomosis was created. The delayed biopsy report showed a moderately differentiated infiltrating tubular adenocarcinoma located in the ampulla of Vater, with focal infiltration of the muscularis propria. The tumor size was 0.8 cm × 0.2 cm, with no vascular or perineural involvement; 0 of 7 peripancreatic lymph nodes were positive for neoplasia (Figure 2).

Figure 2 Histology. An intraoperative frozen section was obtained from peritoneal mesentery. It evidences a carcinoma. The other samples were taken from the primary tumor and analysed in a delayed study. The hematoxylin-eosine stain shows an ampullary adenocarcinoma. The immunohistochemical study evidences an ampullary adenocarcinoma with mixed profile. Intense positivity for caudal-related homeobox transcription factor 2, cytokeratin 20 are indicative of intestinal type differentiation, while positivity for carbohydrate antigen 19-9, epithelial membrane antigen and mucin 6 demonstrate minor biliopancreatic differentiation. Mucin 5AC and cytokeratin 7 markers can be seen in both histologic types. (All the histological images were taken using a 20 × objective). FS: Frozen section; HE: Hematoxylin-eosine stain; CDX2: Caudal-related homeobox transcription factor 2; CA 19-9: Carbohydrate antigen 19-9; MUC6: Mucin 6; MUC5AC: Mucin 5AC; CK7: Cytokeratin 7; EMA: Epithelial membrane antigen; CK20: Cytokeratin 20.

OUTCOME AND FOLLOW-UP

The patient was followed up every 3 months for the first 2 years, and then every 6 months. During this period, physical examinations, laboratory tests, CT scans, and positron emission tomography scans were performed. Colonoscopies were performed and detected hyperplastic polyps, which were resected. A left tonsillectomy was done during his follow-up with a benign biopsy result. During 2023, the patient developed pancreatic insufficiency requiring supplementation with exogenous pancreatic enzymes and beginning with insulin. He achieved 5 years of overall survival (OS) in August 2024, and 4 years of disease-free survival (DFS) in September 2024.

DISCUSSION

This review describes the only case in the literature of ampullary cancer with synchronous peritoneal metastases, with OS of 5 years and DFS of 4 years.

The anatomy of the ampulla of Vater is complex. It is a transition zone between the intestinal epithelium of the duodenum and the pancreatobiliary epithelium from the pancreatic and biliary ducts. When tumors are restricted to the ampulla, compromising until the muscularis propria of the duodenum (T2) without lymph node and distant metastasis, an ampullectomy (endoscopic or open, depending on the features of the patient) could be recommended. In cases of more extensive tumors, the Whipple procedure with lymph node dissection is recommended. Regardless of the histological subtype of adenocarcinoma of the ampulla, the surgical recommendation is the same. For tumors other than those located in the ampulla of Vater, the indication is also the Whipple procedure. Thereby, the anatomic classification defines which procedure the patient needs. To summarize, an ampullectomy is only recommended in the initial stage. In more advanced stages and with the possibility of the abovementioned differential diagnoses, the Whipple procedure should be performed. The latter procedure was performed during a second surgical session, after resection of synchronous peritoneal metastases in the first surgical session. The presence of peritoneal metastases was an indicator of distant dissemination and the reason for performing the Whipple procedure[2,8].

The therapeutic systemic strategy employed, based on the histological study, is another advantage. It facilitates an extrapolation to the possible conduct that would have been taken in another cancer of the gastrointestinal tract. There is biological plausibility, described in the literature, of our selection of systemic therapy and the favorable response to it. The finding of peritoneal carcinomatosis was an indirect sign of disseminated disease, which required control with systemic agents. The FOLFOX regimen was chosen based on the predominant intestinal tumor type, according to immunohistochemical analysis. Studying the presence of mutations such as KRAS allows the identification of patients who would likely benefit from targeted therapies using monoclonal antibodies. In addition, studying microsatellite instability opens the door to treatment with immunotherapy. Neither of those treatments were used in the current case report. Nowadays, the histological and immunohistochemical features of a tumor are more relevant for the indication of a specific systemic treatment than the anatomical location of the neoplasia[7]. In the current case, reduction of the tumor mass after chemotherapy and the absence of neoplasia in lymph nodes, as evidenced by a favorable response to the treatment, is in accordance with studies in other types of gastrointestinal adenocarcinomas in which neoadjuvant therapy reduced tumor size and node positivity[9-11].

Resection of the peritoneal lesion, without the addition of concomitant hyperthermic intraperitoneal chemotherapy (HIPEC), is in accordance with the last evidence about this topic in digestive tumors. This strategy was supported by the results shown in the French multicenter trial, Prodige 7, which enrolled 265 patients with metastatic colorectal cancer with peritoneal metastases. All patients received systemic chemotherapy. They were randomized into two arms: Cytoreduction surgery (CRS) + HIPEC (133 patients) and CRS alone (132 patients). The trial concluded that HIPEC did not provide additional survival advantage when combined with CRS in patients with colon cancer[12]. Other studies with a similar group of patients either had limitations that affect the validity and generalizability of the findings, or did not conclude a benefit in adding HIPEC after CRS[13-15]. There are many studies with controversial results on gastric metastatic peritoneal cancer. In January 2024, the results of the GASTRIPEC-I trial, a multicenter German study, was published. The trial failed to demonstrate a significant OS benefit with the addition of HIPEC after CRS compared to CRS alone. Similar to Prodige 7, a subgroup with intermediate extension of peritoneal carcinomatoses could show improvement in OS after the addition of HIPEC after CRS. OS might be influenced by the introduction of new checkpoint inhibitors as systemic therapy. Indeed, the participation in the effect of new systemic therapies on the outcome of resected synchronous peritoneal metastases is unclear in both groups[16]. In hepatocellular carcinoma (HCC), a French multicenter trial analyzed 135 patients with ruptured HCC; 12% of them had peritoneal recurrence, and 6 of 11 patients with exclusive peritoneal recurrence were operated and had an OS of 36.6 months. In selected cases, the combination of resection plus systemic treatment showed better survival results than systemic treatment alone[17]. For pancreatic adenocarcinoma, there is no evidence supporting CRS with/without HIPEC. There is only evidence of conversion therapy in some selected cases with metastatic disease[18-20]. Patients with biliary tract cancer and synchronous peritoneal metastases receive palliative chemotherapy and best supportive care[21]. At present, the most widely accepted indication for adding HIPEC to CRS in digestive tumors with peritoneal metastases is in cases of peritoneal mucinous carcinoma arising from an appendiceal carcinoma[22].

CONCLUSION

In summary, we presented a patient with adenocarcinoma of the ampulla with intestinal predominance, and with synchronic peritoneal metastases resected, who showed a favorable response to chemotherapy. After discussion in a multidisciplinary committee, he underwent surgery, achieving R0 resection and long-term DFS. Based on the above findings, we do not suggest initially classifying these cases as out of therapeutic reach. Finally, an important value of this work is the individualized treatment of a patient with cancer, based on adequate preoperative study, and the continuous control of the patient.

ACKNOWLEDGEMENTS

Dr. Marta Palma, Former Head of the Medical Oncology Department at Hospital del Salvador, was involved in the strategic planning of the treatment of the patient. She authorized the administration of chemotherapy, and she was the first oncologist to treat the patient. She ceded her position of authorship to the following oncologist. Dr. Jorge Muñoz, an endoscopic surgeon at Hospital del Salvador, provided some conceptual ideas and contributed to clinical follow-up of the patient. Dr. Carlos León, an endoscopic surgeon at Clínica Dávila-Vespucio, is appreciated for implementing the first upper digestive endoscopy and capturing the first endoscopic images, which are presented in this article. Dr Ricardo Urtubia, an anesthesiologist at Clínica Dávila – Vespucio and experienced reviewer for scientific journals, helped with the grammar and spelling correction of the manuscript.