—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 3 - Ossifying Nested Stromal-epithelial Tumor of the Liver

Hala R. Makhlouf
Armed Forces Institute of Pathology (AFIP)
Washington, DC


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Clinical Summary:
This 28 year old woman presented with a solitary liver mass. She had a history of calcified hepatic nodules, believed to be calcified hemangioma, since childhood (age 4). There was a history of contraceptive steroid use. Imaging studies demonstrated a 15 cm circumscribed multi-lobulated lesion arising form segments IV, V and VI of liver. Serum alpha-fetoprotein was normal. Serology for hepatitis A, B, and C was negative. A trisegmentectomy (segments IVB, V, VI) with a wedge resection of a separate focal nodular hyperplasia from segment VII was performed.


Case 3 - Slide 1
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Case 3 - Figure 1
A low power view of the peripheral portion of the tumor.
Case 3 - Figure 2
Tumor with a desmoplastic stroma.
Case 3 - Figure 3
Higher power view of spindle cells and entrapped ductules.

Case 3 - Figure 4
Tumor cells surrounded by a collar of ductules.
Case 3 - Figure 5
Area of calcification and ossification.
Case 3 - Figure 6
Tumor cells positive for pancytokeratin.

Pathological Findings:
Grossly, the tumor was a 14.5x12.5 x8.5 cm circumscribed, lobulated tan and firm mass with scattered small calcifications. Microscopic examination showed a neoplasm composed of islands of spindle and epithelioid cells which ranged from basophilic, to clear, to eosinophilic cells. These islands of cells had an irregular, sharply circumscribed nest-like arrangement in a variably cellular desmoplastic stroma. Focal areas of pseudorosette formation were also present in the tumor. The junction of the epithelial islands with the supporting fibrous stroma revealed a collar of tubular glands that represented a bile ductular component, most prominent at the periphery of the tumor. The cellular stoma surrounding the nests consisted of myofibroblasts (expressing smooth muscle actin) and fibroblasts. Areas of myxoid degeneration, necrosis, and focal psammoma-like calcifications were present with dense osteoid-like collagen and osseous metaplasia. Mitotic activity varied from 1 to 5 mitoses per 10 HPF. Microscopic areas of extension of the tumor into the surrounding liver in a multifocal pattern were present, but there was no vascular invasion. Immunohistochemically, the neoplastic cells within the nests tumors were positive for keratin cocktail AE1/AE3, CAM 5.2 and focally positive for CK19, EMA, and CD56. Tumors cells were negative for CK 8, 18, 20 and 7, but the latter highlighted the ductular component at the edge of the tumors. Tumor cells were strongly positive for vimentin, NSE, and WT-1, the latter showing diffuse nuclear and cytoplasmic staining, but immunostains for desmin, chromogranin, synaptophysin, Leu 7 (CD57), HepPar-1, pCEA, mCEA, S-100 protein, alpha fetoprotein, HMB-45, CD99 CD34, KIT (CD117), estrogen receptor protein, progesterone receptor protein, inhibin, TTF-1, calretinin, ACTH, serotonin, somatostatin, and calcitonin were negative. Ki-67 was positive in 70 nuclei/HPF. The tumor was also negative for SYT-SSX, EWS-WT1, EWS/PNET fusion transcripts by real time PCR and FISH.

Diagnosis:
Ossifying Nested Stromal-epithelial Tumor of the Liver

Subsequent Clinical History:
Six years following her initial resection, the patient developed a solitary intrahepatic recurrence that was treated by radiofrequency ablation This was followed by a second recurrence 20 months later, but the patient is currently alive and well with no evidence of disease 14 years after the initial excision.

General Information:
ONSET represents a rare and unique clinicopathologic entity whose histogenesis and malignant potential remain uncertain. A review of the English literature yielded only 2 reports of 10 well documented cases and another 3 briefly described cases in the AFIP fascicle, which were labeled as " desmoplastic nested spindle cell tumor of the liver" (four cases, patient age range 2-24 years), "nested stromal epithelial tumor of the liver" (six cases, patient ages 2-4 years, two cases associated with Cushing's syndrome) and "ossifying stromal epithelial tumor" (three cases, patient age range 19-32 years). One of the latter 3 cases was also reported by Heywood G et al with a different name "ossifying malignant mixed epithelial and stromal tumor of the liver".

Differential Diagnosis:
The differential diagnosis of ossifying nested stromal-epithelial tumors of the liver (ONSET) includes desmoplastic small round cell tumor (DSRCT), synovial sarcoma, metastatic KIT-negative GIST, primary or metastatic spindle cell sarcomatoid carcinoma, and metastatic primitive gonadal stromal tumor. The histologic features are somewhat reminiscent of the desmoplastic small round cell tumor occurring within the abdomen, not related to a particular organ system , central nervous system. However, most desmoplastic small round cell tumors have occurred in adolescent males, and they typically have a highly aggressive behavior, unlike ONSET. T he only DSRCT that was considered to originate in the liver occurred in a 10-year-old boy who presented with a mass in the right lobe of his liver and bilateral lung metastases. Histologic features in our case (and the previous reported cases) that have not been described in small round cells cases are the formation of tubular glands and the extensive calcification. Also, previously reported cases of the round cell tumor of the abdomen, pleura, or liver have shown immunoreactivity to desmin. Moreover, t he presence of the fusion of the Ewing's sarcoma gene (EWS1) to the Wilms' tumor suppressor gene (WT1) is a feature that is considered unique to DSRCT. Although, a strong reactivity for the WT1 protein in this case studied by immunohistochemical methods were obtained, our molecular real time PCR studies for t (11;22) EWS/WT1 was negative. In addition to DSRCTs, WT1 protein expression has also been reported to occur in Wilms' tumors, renal cell carcinomas, mesotheliomas, papillary serous carcinomas, and in some leukemias.

Areas of glandular and pseudorosette formation was seen in one tumor and when these occur, the distinction from Ewing sarcoma/PNET (primitive neuroectodermal tumor) group of tumors is rather challenging In those cases, the negative immunohistochemical reaction toCD99 would allow separating the two. Because CD99 is expressed in the large majority (80%-100%) of Ewing's sarcomas (EWSs) and peripheral primitive neuroectodermal tumors (PNETs), immunostaining for this marker has been found to be useful in distinguishing these tumors from other small cell neoplasms. Moreover, detection of the fusion transcript of the EWS and PNET genes appear to be helpful in the diagnosis of these tumors. The tumor in discussion was negative for CD99 or for EWS/PNET fusion.

Mixed epithelial and mesenchymal hepatoblastoma and teratoid hepatoblastoma may have admixed bone or osteoid, an important diagnostic consideration in very young patients. However, no staining for HepPar-1 or AFP could be demonstrated in the present tumor, excluding hepatoblastoma.The absence of a demonstrable carcinoma component helps exclude the diagnosis of sarcomatoid carcinoma, and SYT-SSX fusion transcript assay can help differentiate these lesions from synovial sarcoma. The present tumor proved negative for SYT-SSX fusion transcripts. Likewise, Hill et al studied one case by RT-PCR and found it to be negative for the SYT-SSX rearrangement of synovial sarcoma. In contrast to ONSET; GISTs usually have perinuclear vacuolization and often distinct nuclear palisading. In some cases, GISTs are positive for keratins, especially keratins 18 and to lesser degree, keratin 8, and this can complicate the differential diagnosis from ONSET. However unlike GIST, CD34-positivity does not occur in ONSET. Negative immunohistochemical stains for inhibin, ER, and PR in ONSET can help in the differential diagnosis with metastatic primitive gonadal stromal tumor. Teratoma is also raised in the differential diagnosis of ONSET, but the latter does not contain clearly defined respiratory, embryonic or mature anatomic structures and does not seem to grow as an expansile mass, as would be expected of a teratoma.

References:
  1. Heerema-McKenney A, Leuschner I, Smith N, Sennesh J, Finegold M. Nested stromal epithelial tumor of the liver: six cases of a distinctive pediatric neoplasm with frequent calcifications and association with Cushing syndrome. Am J Surg Pathol 2005; 29:1-9.

  2. Heywood G, Burgart LJ, Nagorney DM. Ossifying malignant mixed epithelial and stromal tumor of the liver: a case report of a previously undescribed tumor. Cancer. 2002; 94:1018-1022.

  3. Hill DA, Swanson PE, Anderson K, Covinsky MH, Finn LS, Ruchelli ED, Nascimento AG, Langer JC, Minkes RK, McAlister W, Dehner LP. Desmoplastic nested spindle cell tumor of liver: report of four cases of a proposed new entity. Am J Surg Pathol 2005; 29:10-20.

  4. Ishak KG, Goodman ZD, Stocker JT. Miscellaneous malignant tumors (chapter 11). In: Rosai J, Sobin LH, eds. Tumors of the Liver and Intrahepatic Bile Ducts. Washington, DC: Armed Forces Institute of Pathology, 2001:271-278.

  5. Makhlouf HR, Abdul-Al HM, Goodman ZD. Ossifying nested stromal-epithelial tumor (ONSET) of the liver-A clinicopathologic and immunohistochemical study of 8 cases (abstract) Mod Pathol 2008; 21 (S 1):310A.