Hepatocellular carcinoma with rhabdomyoblastic differentiation

An extremely unique case of a liver tumor occurring in a 70‐year‐old man is documented in this article. The primary tumor was well encapsulated by a thick, connective capsule and was histologically composed of two distinct elements, i.e., a common hepatocellular carcinoma (HCC) and a rhabdomyosarcoma. Metastasis of HCC was only seen in the left adrenal gland, whereas intrahepatic metastatic foci as well as tumor thrombi occluding the portal vein branches were composed exclusively of rhabdomyosarcoma. The possibility that the rhabdomyoblastic component might have come from the preexisting HCC by way of metaplastic proliferation is discussed.

On admission the patient complained of abdominal distension. There was no jaundice, and liver function tests were almost within normal range (total bilirubin, 0.8 mg/dl; glutamic oxaloacetic transaminase, 3 1 KU; glutamic pyruvic transaminase, 20 KU; lactate dehydrogenase, 507 WU; alkaline phosphatase, 10.9 KAU). There was no history of blood transfusions, alcohol abuse, or exposure to toxic agents. Hepatitis B virus (HBV) surface antigen was negative in the serum. However, the level of serum alpha-fetoprotein was elevated to 3 100 ng/ml. An abdominal echogram revealed a high density area in the right lobe of the liver, splenomegaly, and small amounts of ascites. Computerized tomography also showed multiple tumors in the right lobe of the liver. Based on these findings, HCC was clinically suspected. Hepatic arteriography could not be performed due to his poor general condition. Treatment with an antineoplastic agent was immediately excluded because of severe side effects, precluding further treatment as well. By the end of March, renal function became even poorer (creatinine, 3 mg/dl; BUN, 87 mg/dl), and progressive neurologic deterioration was observed. The clinical course went rapidly downhill, and he died on April 7, 1986.

Autopsy Findings
The liver weighed 2280 g and was the seat of an advanced stage of mixed nodular cirrhosis with slight jaundice. The primary tumor, measuring 4 cm in diameter, was present in the right lobe and was independent of the gallbladder, common bile duct, and diaphragm ( Fig. 1). It was roughly spherical and fairly well-circumscribed by a thick capsule. The lesion was dry, firm, and yellowish brown in color due to diffuse coagulation necrosis. Intrahepatic secondary nodules were predomi-78 1 782 CANCER August 15 1988 Vol. 62 nantly deposited in the right lobe. They varied in size from 1 to 20 mm, and their bulging surface presented a somewhat glistening, gelatinous, white appearance. Remarkable distension of the portal vein branches by tumor thrombi frequently occurred, and a retrograde thrombus extended beyond the confluence of the supenor mesenteric and splenic vein. Metastasis to regional lymph nodes was noticed. In the left adrenal gland we also observed a metastatic lesion, which was a soft, friable, gray-white mass with a somewhat different appearance from that of the intrahepatic metastases. Despite detailed examinations, no other tumors or tumor-like lesions could be found in any other organs.
Additional findings included an enlarged spleen weighing 285 g, slightly contracted kidneys showing a finely granular surface with many depressed scars, and severe atherosclerosis of the aorta as well as the coronary artery.

Histologic Findings
The primary tumor was well encapsulated by thick, highly hyalinized connective tissue and had undergone extensive coagulation necrosis. Within the lesion tumor cells were barely preserved in a very limited peripheral area showing aggressive capsular invasion. They consisted of three different cellular elements. First, there were clusters of large polygonal or fusiform cells with abundant eosinophilic cytoplasm that had a large, often bizarre nucleus with a distinctive nucleolus. These tumor cells exhibited solid and sheet-like proliferation FIG. I. A cut surface of the cirrhotic liver. The primary tumor with a thick capsule (thick arrow) is present in the right lobe. Numerous secondary nodules and a large tumor embolus within a portal vein branch (thin arrow) are also seen. and were usually centered by a dilated blood vessel. In places the tumor cells showed a rosette-like arrangement (Fig. 2). Their overall features seemed to be quite consistent with those of Grade I11 HCC (Edmondson and Steiner's classification'). Second, the majority of tumor cells, however, also displayed other characteristics that are compatible with rhabdomyosarcoma, as will be later described in detail. Third, there were some scattered clusters of oval or round cells with scanty cytoplasm presenting a highly undifferentiated appearance. These three types of tumor cells were intimately intermingled, suggesting the possibility that the undifferentiated cells were those of an intermediate form between HCC and rhabdomyosarcoma ( Fig. 3).
All of the metastatic foci in the liver and lymph nodes as well as the tumor thrombi in the portal vein branches consisted of alternating highly cellular areas and less cellular myxoid areas. The tumor cells usually showed remarkable pleomorphism and significant mitotic activity and contained periodic acid-Schiff (PAS) stainingpositive, finely granular materials that could be removed by diastase digestion. There were many spindle or straplike cells that were occasionally arranged in a fascicular or a whorled pattern with few, if any, interstitial collagen fibers. Longitudinal myofibrils and distinct cross striation characteristically could sometimes be identified in their elongated cytoplasm (Fig. 4A). Associated with these cells were a considerable number of large, round or globular cells with deeply eosinophilic cytoplasm (Fig.   4B). Some multinucleated giant cells and multivacuolated bizarre cells were also encountered. The skeletal muscle differentiation of these tumor cells was further confirmed by the ultrastructural demonstration of actin and myosin filaments. Immunohistochemical procedures also revealed the presence of myosin, although actin could not be detected. In terms of ultrastructure, in plump eosinophilic cells thick, 10-15-nm myosin filaments measuring about 1300 'nm in length were assembled in parallel bundles (Fig. 5A).

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Thin 6-to 7-nm actin filaments were rarely discernible, but a regular lattice of both filaments in hexagonal arrangements could be seen in the transverse sections (Fig.   5B). Small, round cells and stellate cells with pyknotic nuclei were scattered in the loose myxomatous, alcian blue-positive matrix.
In the metastasis of the left adrenal gland, tumor cells displayed a macrotrabecular pattern with anastomosing
Both immunohistochemical examinations and Shikata's orcein staining failed to detect surface or core antigens of HBV in any tumor cells or in cirrhotic liver cells. The presence of alpha-fetoprotein also could not be immunohistochemically demonstrated despite its extraordinarily high titer in the serum.
With regard to diabetes mellitus, both kidneys pre- sented typical features of Kimmelstiel-Wilson glomerulosclerosis; the pancreas showed no specific histologic alterations.

Discussion
Rhabdomyosarcomas constitute a complex group of neoplasms of unsettled histogenesis of various adult and embryonal forms. The tumors develop not only in relation to the skeletal muscle, but also in areas in which normally striated muscle tissue is either scanty or absent as in the genitourinary head and neck region4 (particularly the nasopharynx, orbit, and middle ear), and common bile In addition, focal rhabdomyoblastic differentiation occurs as an ingredient of a variety of malignant tumors. In any case, previously reported primary liver tumors containing striated muscle fibers are extremely rare, but they may include rhabdomyosarcoma,6 malignant mixed tumor' (containing hepatoblastoma with rhabdomyoblastic differentiat i~n * *~) and teratoma." Our case is characterized by the coexistence of HCC and rhabdomyosarcoma in the primary hepatic lesion along with intervening undifferentiated cells that showed features characterizing the transition into the two more mature derivatives. There can be several possibilities for this unique lesion: these two elements are (1) the result of dual differentiation of an immature malignant cell, namely a specific variant of malignant hepatic mixed tumor, (2) transformation of HCC into rhabdomyosarcoma, or (3) the reverse course of (2). Our case seems most likely to be a malignant mixed tumor.
By definition, malignant hepatic mixed tumor demonstrates on histologic examination the characteristic components of epithelial and mesodermal structures, either or both of which are malignant. The assemblage of mesodermal derivatives may contain cartilage, bone and/or osteoid, but rhabdomyoblastic differentiation is unusual. However, in rare instances the sole mesodermal derivative may exhibit the form of rhabdomyosarcoma. In fact, Goldman and Friedman" reported the only case of such a tumor interpreted as "rhabdomyosarcohepatoma," occurring in a 65-year-old woman. The tumor was composed of rhabdomyosarcoma in combination with usual HCC and rare foci of bile duct carcinoma. It also comprised primordial cells that were supposed to give rise to the more differentiated neoplasms.
However, according to Edmondson's classification of primary liver tumor," it was emphasized that the mesenchymal portion of malignant mixed tumor is intimately admixed with carcinoma cells throughout its growth as every low-power field usually reveals both elements. It was also stressed that the epithelial tumor element also usually contains heterogeneous components such as adenocarcinoma and squamous cell carcinoma. In view of the various histologic manifestations, it appears that a unifying concept that accounts for the pathogenesis of malignant mixed tumors is still not available.
In the current case there was a thick, hyalinized connective tissue capsule as can be commonly observed in HCC. Such a definite capsule may be a sign of relatively slow-growing tumors if they are malignant. It is therefore unlikely that rhabdomyosarcoma, a highly malignant tumor with a marked tendency to local and regional extension particularly in the liver, had already been present during the early stage of the tumorigenesis.
Of the aforementioned pathogenetic considerations, we favor the second possibility-that HCC cells might have changed themselves into multipotential immature cells, which in turn redifferentiate into rhabdomyoblastic cells for yet unknown reasons. Such a concept, the epithelial origin of the sarcomatous components, has recently been proposed by Weidner and Zekan'' in the occurrence of colon carcinosarcoma. In laboratory studies Tsao and G r i~h a m '~ confirmed that chemically transformed, clonally derived epithelial cells from the adult rat liver are multipotent in nature and capable of differentiating along a variety of epithelial and mesenchymal lines. Whatever the events, the rhabdomyoblastic element presented a more exaggerated growth activity than HCC, implying that this rare malignancy has a poor prognosis.
There is no doubt in the validity of the causal relationship between the development of HCC and several etiologic factors such as chronic HBV infection and ingestion of hepatocarcinogens in food, In our case, as mentioned in his medical history, there was no history of hepatitis, blood transfusions, alcohol abuse, or exposure to toxic agents. In addition, HBV is unlikely to contribute to the occurrence of the tumor from serologic and immunohistochemical aspects. The pathogenesis of the liver cirrhosis thus remained unknown.
Hepatocellular carcinoma often shows considerable morphologic variations including the so-called sarco-matous variety. Our experience suggests that, whether the coexistent sarcomatous component represents a true sarcoma or a metaplastic expression of HCC, this subject may become a more serious issue in the future and that more detailed studies on various similar cases would lead to a clarification of its morphogenesis.