Ruptured Adenosquamous Cell Carcinoma of the Gallbladder: Case Report and Review of Literature

CASE REPORT

A 74-year-old woman presented with a week-long history of progressive right upper quadrant (RUQ) abdominal pain. She reported a 5-pound weight loss over the past few weeks associated with anorexia. She denied any nausea, vomiting, dysphagia, odynophagia, or alterations in bowel habits. She had no history of fever or jaundice. Her past medical history was significant for hypertension, cholelithiasis, and polymyalgia rheumatica. She denied smoking, alcohol use, and illicit drug use. Her mother died of complications of breast cancer at the age of 38.

Pertinent physical examination findings included fever (101° F) and hepatomegaly with RUQ tenderness, without rebound tenderness, guarding, or rigidity. Laboratory studies showed marked leukocytosis (23.8 × 10⁹/L) with neutrophilia (91%). Liver function test results were within normal limits. Ultrasound of the abdomen revealed a large, hypoechoic, ill-defined, lobulated, heterogenous mass (9.0 × 4.2 × 11.2 cm) arising from the region of the gallbladder fossa. Multiple gallstones were seen within the gallbladder without intra- or extrahepatic biliary ductal dilatation. Nuclear biliary tract imaging showed a normal concentration of radioisotope within the liver with a relative region of photopenia within the right lobe and nonvisualization of the gallbladder. Contrast-enhanced computed tomography (CT) scan of the abdomen revealed a multiloculated, peripherally enhancing cystic hepatic mass (11 × 10 × 10 cm) with its epicenter surrounding gallbladder fossa. The gallbladder appeared massively distended with irregular wall thickening (Figure 1).

Figure 1.

Computed tomography scan of the abdomen demonstrates a peripherally enhancing cystic hepatic mass arising in the region of gallbladder fossa.

The patient was started on parenteral broad-spectrum antibiotics for presumed hepatic abscess. Subsequently, she underwent a CT-guided catheter placement and drainage of purulent material, which grew Streptococcus and Gemella species (Figure 2). Fluid cytology revealed scant, markedly atypical cells with squamoid features in the background of abundant acute inflammation suggesting necrotic tumor with squamous differentiation (Figure 3).

Figure 2.

CT scan of the abdomen showing percutaneous catheter placement for drainage of the suspected hepatic abscess.

Figure 3.

Fluid cytology shows groups of atypical, malignant-appearing cells with squamoid features in the background of marked acute inflammation.

Follow-up CT scan of the abdomen revealed persistent cystic lesion with mild decrease in size. Ultrasound-guided fine-needle aspiration (FNA) of the hepatic lesion showed cohesive groups of epithelioid and spindled malignant cells with dense squamoid cytoplasm positive for CK34BE12 and p63 and negative for CA19-9 (Figure 4). A positron emission tomography (PET)-CT scan showed intense [18F]-fluorodeoxyglucose (FDG) uptake in segments 5 and 6 of the liver, with central photopenia corresponding with cystic lesion with central necrosis and no other focus of disease (Figure 5). She underwent diagnostic laparoscopy with excision of subhepatic mass and extended right hepatic lobectomy and trisegmentectomy. Intraoperatively, multiple gallstones were found in the abdominal cavity and a ruptured gallbladder that was contained by the omentum, transverse colon, and mesocolon. A large amount of necrotic material was present, which could be examined directly through what was once the posterior wall of the gallbladder. The peritoneal cavity was visualized, and there was no evidence of peritoneal carcinomatosis.

Figure 4.

Liver FNA demonstrates cohesive groups of malignant epithelioid and spindled cells with dense keratinized cytoplasm. Squamous differentiation was confirmed immunocytochemically, using CK34BE12 and p63; a CA19–9 immunostain was negative.

Figure 5.

PET-CT shows intense FDG-uptake in liver segments 5 and 6 with central photopenia. No additional abnormal FDG uptake suggestive of distant metastatic disease is seen elsewhere in the body.

Pathologic examination of the surgical specimen revealed a large, necrotic cavitary defect (5 cm × 4 cm) along the inferior surface of the gallbladder in the region of the gallbladder fossa that eroded into the liver to a depth of 3.5 cm. The surface of the eroded defect was replaced by shaggy, grey-white tumor mass with scattered, embedded tan-yellow faceted calculi. The sectioned liver parenchyma showed a dominant, grey-white to yellow, partially necrotic mass (15.0 × 10.0 × 6.0 cm) in the region of the gallbladder fossa defect extending from the defect to the intact superior hepatic capsule.

The tumor was identified as a poorly differentiated adenosquamous carcinoma on histopathology (Figure 6). Immunohistochemical staining was positive for MOC-31 (marker for adenocarcinoma) and CK-19 (marker associated with pancreatobiliary tumors) (Figure 7). Hepatocyte-antigen, Glypican-3, CEA-polyclonal staining were negative. There was no evidence of vascular or perineural invasion, but carcinoma focally abutting the hepatic resection margin and a single lymph node with possible secondary invasion by tumor was identified. The tumor was staged pT3pN1. The patient's postoperative course was free of complications, and she was discharged to her home with subsequent follow-up.

Figure 6.

Histopathology shows sheeted squamoid cells admixed with foci of glandular differentiation, yielding a diagnosis of adenosquamous carcinoma.

Figure 7.

Membranous immunohistochemical staining using MOC-31 demonstrates glandular differentiation in this carcinoma.

DISCUSSION

Although characterized by a relatively simple microscopic anatomy, the gallbladder may give rise to a wide histopathologic variety of malignant tumors. Gallbladder carcinoma is a relatively rare and lethal gastrointestinal malignancy, with the majority of cases being adenocarcinoma.^1–3 Primary carcinoma of the gallbladder includes the following histologic types in decreasing order of incidence: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, and oat cell carcinoma.⁴ Adenosquamous or squamous carcinoma is a rare histopathologic subtype, accounting for an estimated 5.3–10.6% of all incidences of gallbladder carcinoma.^4–6

Regardless of histopathologic subtype, gallbladder carcinoma is a highly lethal disease, and outcomes following surgical treatment remain dismal.^7–9 The prognosis remains poor across subtypes, mainly due to a lack of specific presentations and typically advanced disease stage at diagnoses, which greatly compromises or precludes the potential for curative resection.^10,11

Clinical Presentation

Patients with adenosquamous cell carcinoma of the gallbladder most commonly present with a large mass replacing the gallbladder fossa.^12,13 The bulky tumor is usually diagnosed at an advanced stage,^5,14–16 with frequent invasion of the neighboring organs, such as the liver, duodenum, stomach, colon, pancreas, and extrahepatic bile duct.^6,11,17 The liver is the most common site of invasion,¹² and one tends to see a higher proportion of liver infiltration in patients with advanced adenosquamous carcinoma vs. advanced adenocarcinoma of the gallbladder, a difference that reaches statistical significance.¹⁰

In one retrospective study, 70% of all enrolled patients with gallbladder carcinoma presented with advanced stages (pT3 and pT4), and all patients with adenosquamous or squamous cell carcinoma were staged either pT3 or pT4.¹⁰ In another study by Oohashi et al, 79.3% of adenosquamous carcinoma cases were found to be T3 or T4 with invasion of adjacent organs.¹¹ Spontaneous gallbladder perforation with peritonitis was reported in two patients. Marked infiltration of neutrophils within the tumor was seen in 86.2% of cases. The patient described in this case report had marked neutrophilic infiltration, and during surgical resection it was discovered that her gallbladder had ruptured.

Pathology

Adenosquamous carcinoma is a moderately differentiated neoplasm composed of two malignant components. One is glandular (mucin) and the other squamous (keratin).¹⁸ The origin of the squamous cell component is thought to be metaplasia of the adenocarcinoma.^19,20 Charbit et al reported that the squamous component grows twice as fast as the adenocarcinomatous component (doubling time, 81 days vs. 166 days, respectively).²¹ Nishihara et al demonstrated that the squamous component of adenosquamous carcinoma of the gallbladder has a greater proliferative capacity compared with the glandular component.^5,22 This explains the frequency of bulky tumor and adjacent organ involvement in patients with adenosquamous/squamous cell carcinoma of the gallbladder.

Squamous cell carcinoma of the gallbladder has been reported to spread primarily by direct extension, with fewer metastases to the lymph nodes or other organs, suggesting that the metastatic potential of this rare tumor may be lower compared with the metastatic potential of adenocarcinoma.^15,16,23 In this context, theoretically, adenosquamous and squamous cell carcinoma of the gallbladder appear more suitable for resection than does adenocarcinoma. However, the high frequency of local invasion associated with this tumor and the typically advanced stages at the time of initial diagnosis often precludes resection. This might explain why the prognosis for patients with adenosquamous or squamous cell carcinoma of the gallbladder is poorer compared with the prognosis for patients with adenocarcinoma.

Prognosis

Patient outcomes after resection for adenosquamous or squamous cell carcinoma of the gallbladder are generally poor.^4,5,17,19,24 Oohashi et al reported that survival after undergoing radical resection was significantly better compared with survival after undergoing primary tumor resection alone.¹¹ In 16 patients who underwent radical resection, the median survival was 18 months, with a cumulative 5-year survival rate of 48.6%, compared to median survival of 4 months, with a cumulative 3-year survival rate of 7.7% in 13 patients who underwent primary tumor resection alone (P < .004). Residual tumor status was the only significant independent prognostic factor in this study, suggesting that potentially curative (R0) resection should be pursued whenever patients undergo resection for adenosquamous or squamous cell carcinoma of the gallbladder.