Mixed Adenocarcinoma and Squamous Cell Carcinoma of Duodenum: A Case Report and Review of the Literature.

Despite being the largest part of the human gastrointestinal (GI) tract, the small intestine accounts for only 1-1.4% of all GI malignancies. Adenocarcinoma is the most common primary small bowel malignancy, with the most common site being the duodenum. On the other hand, squamous cell carcinoma (SCC) of the duodenum is extremely uncommon. We report the first case of mixed adenocarcinoma and SCC occurring in the third part of duodenum (D3). Our patient, a 64-year-old female with history of GERD, hypertension, and IDDM presented with 4 weeks of nausea, vomiting, and abdominal pain. Tomographic imaging of her abdomen demonstrated a distended stomach and a proximal duodenum with narrow caliber changes at the level of D3. An EGD revealed a tight stricture at D3 that could not be traversed. Stricture biopsies revealed duodenal mucosa with two small foci of SCC (positive for p63 and CK5/6) and adenocarcinoma (positive for CK7 and Moc31). Peritoneal metastases were detected on exploratory laparotomy, making the tumor surgically incurable. As she progressively declined and with worsening liver enzymes and general debility, she was not a candidate for chemotherapy and was eventually discharged on home hospice. Small bowel SCC/adenocarcinoma is an exceedingly uncommon cancer, making further case reports such as ours important to understand the nature of this entity and establish management guidelines.

Introduction

The small intestine is the largest part of the human gastrointestinal (GI) tract, encompassing nearly 90% of its mucosal surface. Interestingly, it only contributes minimally to the total tumor burden from the GI tract [1]. Only 1–2% of GI malignancies originate from the small intestine; however, the incidence of these malignancies is trending upwards, partly due to increased tumor detection via advanced diagnostic endoscopic and radiographic modalities [1]. The ileum carries the majority of the small intestinal tumor burden, followed by the duodenum, and lastly the jejunum [1]. The majority of duodenal cancers originate from the descending duodenal segment (D2), followed by the horizontal (D3) and ascending (D4) segments, and rarely from the proximal horizontal segment (D3) [2]. More than 40 histological subtypes of small intestinal malignancies have been described, the most common being adenocarcinoma, sarcoma, lymphoma, and neuroendocrine tumors [3]. Rare cases of squamous cell carcinoma (SCC) and mixed tumors like adenosquamous carcinoma (ASC) and adenoneuroendocrine tumors have been reported as isolated case reports [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. ASC of the duodenum is an exceedingly rare neoplasm, with only a few cases described in the medical literature. In the majority of these cases, the tumor originates from the ampulla of Vater. Presentations of patients with duodenal cancer are highly variable and include nonspecific symptoms like abdominal pain, anemia, nausea, and vomiting [16]. We report a patient who presented with altered mental status and persistent nausea and vomiting. She was found to have ASC of the third segment of the duodenum (D3). To the best of our knowledge, this is the first reported case of duodenal ASC arising from the third duodenal segment (D3).

Case Summary

A 64-year-old woman with a history of poorly controlled diabetes mellitus (hemoglobin A1c of 9.3%) and suspected diabetic gastroparesis presented with a 4-week history of nausea, vomiting, bloating, epigastric pain, and a 2-day history of altered mental status. Laboratory testing revealed a blood glucose level of 756 mg/dl, anion gap of 21, β-hydroxybutyrate of 2.8 mmol/L, and positive urine ketones. She was diagnosed with diabetic ketoacidosis and managed accordingly with intravenous fluids and insulin infusion. Despite correction of the ketoacidosis, her symptoms persisted. Further history indicated that the nausea and vomiting had been progressively worsening over the past year. This was thought to be related to underlying gastroparesis, given her long–standing history of uncontrolled diabetes mellitus. An upper endoscopic evaluation performed a year ago was unremarkable. She was started on Metoclopramide with no symptomatic benefit. Contrast computed tomography demonstrated a distended stomach and proximal duodenum, with caliber change at the level of the third portion of the duodenum and minimal adjacent fat stranding (Fig. 1). The dilatation was further assessed with an upper GI barium series demonstrating a segmental constriction of D3/D4, causing high-grade obstruction (Fig. 2). An upper endoscopic evaluation demonstrated a stricture and mucosal abnormality in the third segment of the duodenum (D3), which was biopsied. At that time, a decision was made to initiate total parenteral nutrition to meet her nutrition needs. Pathology from the duodenum revealed duodenal mucosa with two small foci of SCC and adenocarcinoma (Fig. 3). Immunohistochemical staining of the SCC stained positive for p63, weakly CK5/6, and was focally positive for CDX2, and negative for CK20 and Moc31. The adenocarcinoma cells stained positive for CK7, focally positive for CK20, weakly positive for CDX2, and negative for p63 and CK5/6 (Fig. 4). Tumor cells from both foci stained negative for TTF-1 and ER. CD34 and D2–40 stains were positive in the endothelial lining of the lymph-vascular spaces, and no lymphovascular invasion of the tumor cells was seen. About 50% of the tumor cells of the adenocarcinoma and 8% of the tumor cells of the SCC stained positive for Ki67/Mib-1. These findings were consistent with a mixed adenocarcinoma/SCC. Tumor staging with computed tomography of the chest, abdomen, and pelvis revealed no evidence of metastatic disease or other primary malignancy. Locoregional staging with endoscopic ultrasound revealed three enlarged lymph nodes in the peripancreatic and periduodenal region. She underwent an exploratory laparotomy and was found to have peritoneal metastasis with encasement of the middle colic vein and superior mesenteric vein. Tumor staging was upgraded to unresectable advanced stage IV cancer. Curative intent was aborted, and a gastrojejunostomy with gastrostomy for decompression and a feeding jejunostomy were performed. Her postoperative course was prolonged and complicated by intractable vomiting resulting in worsening renal function and progressive malnutrition, severe obstructive jaundice (total bilirubin 8.8 mg/dL, conjugated bilirubin 6.4 mg/dL, and alkaline phosphatase 549 units/L) secondary to a localized stricture in the left hepatic duct. This was identified on endoscopic retrograde cholangio-pancreatography and treated by placement of one plastic biliary stent across the left hepatic duct and well into the left intrahepatic system. Despite improvement of liver enzymes, her debility worsened and she progressively declined. She was deemed to be a poor candidate for chemotherapy and was eventually discharged on home hospice.

Fig. 1

Axial (a) and coronal (b) noncontrast CT images demonstrate asymmetric thickening of the wall of the third part of the duodenum (arrows), resulting in obstruction and marked distention of the stomach (S) and the proximal duodenum (D).

Fig. 2

A spot image of an upper GI examination demonstrating severe constriction (arrow) at the third/fourth part of the duodenum, showing opacification of an irregular and narrowed lumen. The stomach (S) and the portion of the duodenum (D) proximal to the stricture are distended. The portion of duodenum distal to the stricture and jejulum (J) are normal.

Fig. 3

Microscopically, the tumor was composed of adenocarcinoma (a) and squamous cell carcinoma (b). HE. ×400.

Fig. 4

Immunohistochemistry of the adenocarcinoma (AdCa) and squamous cell carcinoma (SCC) components. The tumor cells of AdCa are strongly and diffusely positive for CK7 (a), and focally positive for CDX2 (b, left) and CK20 (b, right). The SCC cells are positive for P63 (c) and CK5/6 (d). a–d ×400.

Discussion

ASC of the duodenum is an exceptionally rare tumor. Histologically, it is composed of a variable combination of glandular architecture in the form of acini/papillae (adenocarcinoma) and squamous architecture in the form of keratinization and intercellular bridges (SCC). Published literature suggests that duodenal adenocarcinomas are largely positive for gastro-pancreatobiliary markers (CK7), and less commonly positive for intestinal markers (CK20, CDX2) [17], similar to the findings in our case. Typical markers to characterize SCC are p63 and CK5/6 [18]. Our patient's tumor cells stained positive for these markers, confirming the SCC component. This, beyond doubt, proves the mixed ASC nature of the tumor described in our case report.

The origin of SCC in the duodenum is debatable, especially since the duodenal mucosa is composed of glandular epithelium with no squamous tissue. There are a few hypotheses to explain this observation: (1) presence of pluripotent stem cells in the mucosa capable of transforming into both adenocarcinoma and SCC components, (2) squamous metaplasia in the intestinal mucosa, and (3) squamous transformation of the adenocarcinoma cells [19]. Bile has been postulated as a potential carcinogen, provoking malignant transformation in the duodenal mucosa, as about 57% of all adenocarcinoma of the small intestine is found in the D2 segment, which is less than 1% of the length of small intestine [20]. Furthermore, evidence from previous studies suggests that the SCC components grow more aggressively than their adenocarcinoma counterparts, as demonstrated by the short doubling time of SCC cells [4]. Thus, the extent of SCC presence in the ASC tumor may be related to the overall tumor progression and can have prognostic implications.

Only 7 cases of primary ASC of the ampulla of Vater [4, 5, 6, 19], 8 cases of primary SCC of the duodenum [7, 8, 9, 10, 11, 12, 13], and 2 cases of primary SCC of the ampulla of Vater [14, 15] have been reported in the medical literature. Clinical characteristics, treatment, and prognosis of all these cases are summarized in Table 1. Based on the reported cases, it appears that ASC and pure SCC of the duodenal region affect both males and females, but the reported number of male cases exceeds female cases by about 2: 1. The majority of these tumors originated from the ampulla of Vater; thus, the most common clinical presentation includes abdominal pain, jaundice, nausea, and vomiting. Surgical resection of the tumor was the predominant treatment modality, but unfortunately the mortality remained very high, approaching 50% within 12 months and 75% within 24 months of diagnosis.

Table 1

Clinical characteristics, treatment, and prognosis of all reported cases of ASC and SCC of the small bowel

First author [Ref]., year	Age, years/gender	Symptoms	Pathology	Treatment	Prognosis, months
Ueno [10], 2002	47/man	Fatigue, jaundice	ASC of AmV	PD	10 (dead)
Yang [7], 2013	82/man	Jaundice	ASC of AmV	Ampullectomy	14 (dead)
Yang [7], 2013	68/man	RUQ pain, jaundice	ASC of AmV	PD	7 (dead)
Yang [7], 2013	34/woman	RUQ pain, jaundice	ASC of AmV	PD	10 (dead)
Yang [7], 2013	77/man	RUQ pain, jaundice	ASC of AmV	PD	6 (dead)
Kshirsagar [11], 2014	58/man	Abdominal pain, jaundice, vomiting, anorexia	ASC of AmV	PD	Notmentioned
Hoshimoto [9], 2015	81/woman	Asymptomatic elevation of liver enzymes	ASC of AmV	Pylorus-preserving PD	20 (alive)
Friedman [12], 1986	61/man	Abdominal pain, weight loss	SCC of D3	Partial duodenectomy and duodeno jejunostomy	4 (alive)
Delius [13], 2006	75/woman	Upper GI bleeding	SCC of D1	Not mentioned	Not mentioned
Diffaa [14], 2012	60/woman	Epigastric pain, melena, weight loss	SCC of D3	Palliative chemotherapy	1 (dead)
Battal [15], 2015	39/man	Epigastric pain, weakness, vomiting	SCC of D3	Surgical resection of duodenal diverticulum harboring SCC	10 (alive)
Terada [16], 2010	75/man	Vomiting, weakness	SCC of D2	Chemoradiation	17 (died)
Terada [17], 2009	58/woman	Abdominal pain	SCC of D2	Chemoradiation	21 (died)
Terada [17], 2009	54/man	Abdominal pain	SCC of D2	Not mentioned	Not mentioned
Pahl [18], 2012	65/man	Epigastric pain, weakness	SCC of D3	PD	60 (died)
Gupta [19], 2009	28/woman	Abdominal pain, jaundice, vomiting	SCC of AmV	PD	Not mentioned
Bolanaki [20], 2014	68/man	Jaundice, fatigue	SCC of AmV	PD	5 (died)

PD, pancreaticoduodenectomy; AmV, ampulla of Vater.

However, no reports of primary ASC originating from the duodenal mucosa were found. Also, we describe the first case of a primary mixed ASC of the third part of the duodenum (D3) presenting with nonspecific symptoms of nausea and vomiting and unfortunately with high metastatic potential and a dismal prognosis. Little is known about the pathogenesis and natural history of this disease, given the rarity of this malignancy. Approach and treatment guidelines remain unestablished. The majority of patients reported presented with jaundice and abdominal pain with survival of about 12 months after diagnosis. General consensus regarding the treatment of these infrequent cancers is surgical resection of the tumor with negative margins, irrespective of the histology. Postoperative chemotherapy and radiotherapy should also be considered especially in tumors with a squamous component, as it confers a worse prognosis. Unfortunately, specific details of the management remain unelucidated given the rarity of these tumors.

In summary, we present the first case of a primary mixed ASC of the duodenum specifically originating from segment D3. Given the rareness of the pure SCC and mixed ASC of the duodenum, very limited information exists in the medical literature regarding the clinicopathological features and ideal management strategies. Further cases of these uncommon cancers need to be identified and reported for better pathological and clinical understanding of these tumors, as well as to gain more insight into different treatment strategies and their overall outcome on the prognosis.

Statement of Ethics

Consent for publication was obtained from the patient.

Disclosure Statement

The authors declare no conflicts of interest.