Abstract Calcifying nested stromal epithelial tumor

Abstract
Calcifying nested stromal epithelial tumor (CNSET) is a recently described primary neoplasm of the liver. This tumor is characterized by well-demarcated nests of spindle and epithelioid cells with occasional calcification and bone formation. An association between these tumors and Cushing syndrome has been described, but there is no clear evidence for the origin of CNSET. We report the case of a 20-year-old male with Klinefelter syndrome who had postoperatively recurrent CNSET that showed aggressive clinical behavior and extrahepatic lymph node metastasis. This case suggests that an imbalance of hormones affects the genesis and progression of CNSET and shows that patients with CNSET must be carefully followed with imaging to detect hepatic recurrence and extrahepatic metastases.

Key words: Calcifying nested stromal epithelial tumor (CNSET); Hormone imbalance; Klinefelter syndrome; Liver; Neoplasm

Core Tip: The genesis and progression of calcifying nested stromal epithelial tumor (CNSET) may be affected by an imbalance of hormones. Patients with CNSET must be carefully followed with imaging to detect hepatic recurrence and extrahepatic metastases.

Tsuruta S, Kimura N, Ishido K, Kudo D, Sato K, Endo T, Yoshizawa T, Hakamada K. Calcifying nested stromal epithelial tumor of the liver in a patient with Klinefelter syndrome
INTRODUCTION
Calcifying nested stromal-epithelial tumor (CNSET) is an extremely rare primary hepatic tumor characterized by a nested morphologic growth pattern of spindled epithelioid cells with potential for variable calcification and/or ossification. Most liver cancer is hepatocellular carcinoma (HCC), followed by intrahepatic bile duct cancer. A non-hepatic, non-biliary tumor resembling CNSET was first described in 2001 by Ishak et al.1 To our knowledge, there are now 38 cases reported in the literature under a variety of names, including ossifying stromal-epithelial tumor, desmoplastic nested spindle cell tumor of the liver (DNSTL), nested stromal epithelial tumor (NSET), and ossifying malignant mixed epithelial and stromal tumor2-23. These tumors have similar morphology, immunohistochemistry and molecular profiles, and Misra et al. suggested that they may be related, but with a spectrum of morphologic features24. The reported tumors have been found predominately in females, and commonly in children, and most arose from the right hepatic lobe. An association between these tumors and Cushing syndrome has also been described in a number of cases. Here, we report a case of postoperatively recurrent CNSET with aggressive clinical behavior and extrahepatic lymph node metastasis in a patient with Klinefelter syndrome.

CASE REPORT
The patient was a 20-year-old male who had been a low-birth-weight infant and had a history of Klinefelter syndrome and pulmonary valve stenosis. He was introduced to our hospital for further examination of a liver tumor that was increasing in size. The tumor had been found incidentally after laboratory findings in a health checkup showed impairment of liver function. The patient had declined treatment due to his employment situation, and had instead been followed up for one year.
At the first visit, he was completely asymptomatic with normal vital signs. A physical examination revealed a palpable right upper mass without tenderness. No evidence of Cushing syndrome was noted. In blood tests, hepatitis B virus surface antigen and hepatitis C virus antibody were negative. Liver function tests indicated mild dysfunction. Regarding tumor markers, serum alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) were normal; however, neuron specific enolase (NSE) was elevated.
Ultrasonography showed a large low-echoic solid tumor with a vertical diameter of >80 mm with partial calcification implied by an acoustic shadow in an anterior lesion of the liver. A computed tomography (CT) scan of the chest, abdomen and pelvis revealed an 81×76×72 mm large, heterogeneously enhanced mass in the right lobe of the liver with dense partial calcification (Figure 1A). Subsequent positron emission tomography (PET)/CT showed a large hepatic mass in the right lobe with a maximum standardized uptake value (SUV) of 22.4 and no extrahepatic metastasis. In magnetic resonance imaging (MRI), most of the tumor was weakly enhanced in T1-weighted images and strongly enhanced in T2-weighted images. Part of the tumor had early enhancement and washout in enhanced MRI. These findings suggested HCC, and especially fibrolamellar HCC, but without evidence of distant metastasis.
Right hepatic lobectomy and cholecystectomy were performed 11 months after the initial detection of the tumor. The patient received no adjuvant radiotherapy or chemotherapy. The postoperative course was characterized by respiratory failure that required reintubation on postoperative day (POD) 2. X-ray and bronchofiberscopy showed pneumoniae due to pulmonary atelectasis and pulmonary edema. The subsequent hospital course was uneventful. On POD 7, a CT scan of the abdomen was interpreted as negative for hemoperitoneum and tumor recurrence, and the patient was discharged on POD 12.
The patient was followed up as an outpatient and received several examinations. On POD 62, a CT scan showed multiple, obscure, circumscribed recurrent lesions in the remnant liver with contrast enhancement. The largest of these lesions had a diameter of 42 mm in segment 1 (S1) (Figure 1B). In addition, a hypermetabolic para-aortic lymph node with possible metastasis was identified. On PODs 70 and 73, the patient underwent transcatheter arterial chemoembolization (TACE), but a second CT scan in the outpatient department on POD 84 revealed enlargement of recurrent tumors and the para-aortic lymph node. Chemotherapy (protocol for HCC) was started, but was unsuccessful because of side effects. At this time, there were no further surgical options and no other chemotherapy that was likely to be effective. Therefore, the patient received palliative care. The patient died 164 days after hepatectomy from tumor progression with development of progressive liver failure.
Grossly, the tumor was confined to the right liver lobe. The resected specimen weighed 1180 g. The lesion had a maximum diameter of 100 mm and was a well-circumscribed solitary mass with multiple small calcifications that were sharply demarcated from surrounding uninvolved liver parenchyma (Figure 2). The surgical margin was tumor-free. Microscopically, the tumor was characterized by an organoid arrangement of cellular nests of epithelioid cells and areas of sheet-like cell overgrowth (Figure 3A). These cells had oval-like nuclei with no clear nucleolus and eosinophilic cytoplasm. Nests of epithelioid cells were surrounded by a spindle-cell framework, and transition zones between epithelioid and spindle cells were identified (Figure 3BC). Bile ducts were not intermingled with the tumor region. There were extensive regions of necrosis and calcification (or ossification) in the center of the tumor (Figure 3D).
In immunohistochemical staining, epithelioid cells were positive for CD56, cytokeratin AE1/AE3 (focal), WT-1 (diffuse or dot-like in cytoplasm), ?-catenin (diffuse in nucleus), vimentin, NCAM, and NSE (Figure 3EF). Spindle cells in mesenchymal components such as the septum were diffusely stained with ?-smooth muscle actin (?-SMA) (Figure 3G). The AFP level was within the normal range. Staining for glypican-3 was negative. The proliferation index on MIB-1 (Ki-67) immunostaining was