Hepatoid Adenocarcinoma of the Urachus

Hepatoid adenocarcinoma of the urachus is a rare condition. We present the case of a 51-year-old female who developed abdominal pain and hematuria. Pelvic magnetic resonance imaging (MRI) reported an urachal mass with invasion to the bladder that was resected by partial cystectomy. On light microscopy the tumor resembled liver architecture, with polygonal atypical cells in nest formation and trabecular structures. Immunochemistry was positive for alfa-fetoprotein (AFP) and serum AFP was elevated. Hepatoid adenocarcinomas have been reported in multiple organs, being most commonly found in the stomach and the ovaries. Bladder compromise has been rarely described in the literature, and it has been associated with poor prognosis, low remission rates, and early metastasis.


Introduction
Hepatoid adenocarcinoma (HAC) is an extrahepatic tumor that is morphologically similar to the architecture of hepatocellular carcinoma (HCC) [1]. On light microscopy, it is composed of large polygonal cells in a nest pattern and occasionally exhibits bile canaliculi formation producing bile pigment [2]. On immunohistochemistry hepatoid adenocarcinomas could be positive for alfa-fetoprotein (AFP), epithelial membrane antigen (EMA), and albumin [3]. Hepatocyte paraffin-1 (HepPar1), glypican-3, and arginase 1 are useful hepatic markers and canalicular patterns can react with polyclonal anticarcinoembryonic antigen (CEA). Elevated serum AFP has been correlated as well with HAC [1,4], but it is not always present [5]. Clinically patients are usually older males presenting with hematuria [6] and tumors can be very aggressive presenting with lung metastases [2]. HAC have been reported in multiple organs but are most commonly found in the stomach and the ovaries [7]. We report the clinicopathological features of a patient with a HAC of the urachus with invasion to the bladder.

Case Report
Our patient is a 51-year-old Latin American female, who presented with a 6-month history of mild generalized abdominal pain and one episode of gross hematuria. On physical examination there was a distended abdomen and pain on deep palpation.
Initial investigations included a transvaginal ultrasound, which revealed a pelvic tumor extending towards the abdominal cavity. Pelvic MRI showed a mass located in the bladder dome that measured 12 × 10 × 11 cm, with heterogenous signal in T2 and a necrotic center ( Figure 1). The exophytic appearance and the mass location were suggestive of a lesion originated in the urachal diverticulum. The mass compromised other structures such as fat and muscle around the bladder, as well as a portion of the ileum, which showed thickening and narrowing of its lumen. Retroperitoneal and iliac lymph nodes were increased in size. No lesions were evident on the bladder neck, trigonum vesicae, or ureters.
Subsequently, the patient underwent a transurethral resection (TUR) for a microscopic diagnosis. The initial pathology reported limited sample with insufficient material 2 Case Reports in Pathology for diagnosis. Due to the tumor characteristics with evident invasion to other tissues, it was considered appropriate to perform a palliative surgery, consistent in partial cystectomy plus partial ileum resection. The pathology report from the partial cystectomy showed an ulcerated and hemorrhagic lesion measuring 11 × 9 × 7 cm macroscopically. Light microscopy revealed a neoplastic proliferation of large polygonal epithelial cells, arranged in a nesting and trabecular pattern, with central necrosis. These cells showed focal pleomorphism, prominent nucleoli, wide eosinophilic cytoplasm, and occasional hyaline PAS positive globules ( Figure 2). More than ten mitoses in ten high power fields were found. The neoplasm showed extensive involvement of the serosa with ileum wall involvement. There was no vascular or neural invasion. However, three lymph nodes were compromised.
All the previous findings were consistent with invasive high-grade hepatoid adenocarcinoma of the bladder originated in the urachus. Stage was T3a N2, with free surgical borders.
After surgery, the patient remained stable, with symptomatic improvement and no further complications. A subsequent abdominal Computer Axial Tomography (CAT) scan ruled out the possibility of a metastatic hepatocellular carcinoma or other abdominal lesions. Serum AFP was elevated.
After four months of surgery, the patient has been treated with three cycles of chemotherapy, with Gemcitabine and Cisplatin, with adequate response and no adverse effects. Serum AFP level at this time is significantly lower compared to previous measurements.

Discussion
Hepatoid adenocarcinoma (HAC) is any epithelial cancer from a nonliver origin, which resembles hepatic cells morphology [1]. One of the most important steps for diagnosis is to rule out extrahepatic metastases of HCC. HAC commonly involve organs such as the stomach and ovaries [7]. In addition, involvement of the lungs, gallbladder, pancreas, uterus, and adrenals has been reported [1,[7][8][9][10][11]. The most common site of metastasis is the lung [2].
In our case the tumor originated from the urachus involving the bladder. This location is very rare. Urachal tumors represent 0,01% of adult cancers and 0,17 to 0,34% of bladder cancers [12,13]. Since 1994, 9 cases of HAC of the bladder have been reported [2, 4-6, 14, 15] and this constitutes the second case of hepatoid urachal adenocarcinoma reported in the literature [16].
In Table 1 we summarize the demographic and clinical data of 10 cases of HAC of the bladder, including our case. According to the details provided, the most common manifestation was hematuria in 8 cases. The average age at presentation was 68 years and 6 of the cases were males. Four patients were staged T3 and 3 patients had metastatic disease at diagnosis. The size of the tumor of our patient was 11×9 cm, bigger than the previously reported cases [4].
Our case is a high-grade/high-stage tumor, different from the usual behavior described of low-grade even in high-stage cases [2,5,6].
On immunohistochemistry, AFP was positive and CEA was negative, as originally described by Prat et al. in hepatoid ovary tumors [17]. We used monoclonal anti-CEA that resulted in being negative, and although positive staining would support the diagnosis due to its high specificity, the result obtained does not rule it out [18]. Other markers as chromogranin and NSE were negative as expected [2,5].  Our patient had a Ki67 proliferation index of 70%. Ki 67 has been characterized as a reliable indicator of muscle invasion and useful in confirmation of high-grade lesions in certain tumors [19]. In our review, a case of a high-grade HAC of the stomach showed elevated Ki67 [20]. However, we need a bigger sample of cases to make a correlation between Ki67 proliferation index and staging in hepatoid adenocarcinomas. This type of tumor has a poor prognosis and low cure rates. The longest survival after diagnosis has been 26 months [2], which has been inversely associated with staging [4,6]. All the patients with metastatic disease at diagnosis have died by the time of the case report [2].
Treatment for HAC in other organs has been characterized [9], but not in the bladder. We consider that the role of chemotherapy requires further investigation, especially in the field of drug resistance expression of ATP Binding Cassette (ABC) and drug transporters in hepatoid adenocarcinomas [21].

Conclusions
In summary, we present a case of hepatoid adenocarcinoma of the urachus with involvement of the bladder. The patient presented with abdominal pain, gross hematuria, and a bladder mass. On light microscopy the lesion resembled the histology of hepatocellular carcinoma. On immunochemistry AFP was positive and serum AFP was elevated.
To our knowledge this is the second case of hepatoid adenocarcinoma of the urachus reported in literature and first case reported in Latin America.