Fibrolamellar hepatocellular carcinoma in children and adolescents

BACKGROUND: Children with hepatocellular carcinoma (HCC) were treated on a prospective, randomized trial and were then analyzed to determine whether children with the fibrolamellar (FL) histologic variant of HCC have a more favorable presentation, increased surgical resectability, greater response to therapy, and improved outcome compared with children who have typical HCC. METHODS: Forty-six patients were enrolled on Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group Study 8945/Children's Cancer Group Study 8881) between August 1989 and December 1992. After undergoing initial surgery or biopsy, children with Stage I HCC (n = 8 patients), Stage III HCC (n = 25 patients), and Stage IV HCC (n = 13 patients) were assigned randomly, regardless of histology, to receive treatment either with cisplatin, vincristine, and fluorouracil (n = 20 patients) or with cisplatin and continuous-infusion doxorubicin (n = 26 patients). RESULTS: Ten of 46 patients (22%) had the fibrolamellar variant of HCC (FL-HCC). For the entire cohort, the estimated 5-year event free survival (EFS) rate (+/- standard deviation) was 17% +/- 6%. There was no difference in outcome among patients who were treated with either regimen. The 5-year EFS rate for patients with FL-HCC was no different the rate for patients with typical HCC (30% +/- 15% vs. 14% +/- 6%, respectively; P = 0.18), although the median survival was longer in patients with FL-HCC. There was no difference in the number of patients with advanced-stage disease, the incidence of surgical resectability at diagnosis, or the response to treatment between patients with FL-HCC and patients with typical HCC. CONCLUSIONS: Children with FL-HCC do not have a favorable prognosis and do not respond any differently to current therapeutic regimens than patients with typical HCC. Children with initially resectable HCC have a good prognosis irrespective of histologic subtype, whereas outcomes are poor uniformly for children with advanced-stage disease. The use of novel chemotherapeutic agents and the incorporation of other treatment modalities are indicated to improve the dismal survival of pediatric patients with all histologic variants of advanced-stage HCC.     

A Case of Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma is an uncommon histologic subtype of hepatocellular carcinoma, comprising 3.5% of all hepatocellular carcinomas in one large study (Brandt et al 1988). It usually occurs in young people, the average age being 18 years (Farhi et al 1983). It is not associated with cirrhosis and the serum alphafetoprotein is usually normal (Craig et al 1980). Fibrolamellar hepatocellular carcinoma has a more favourable prognosis than the usual hepatocellular carcinoma, with an average survival of 32 months from onset of symptoms, compared to 6 months for the usual type. The resectability rate and 5 year survival figures are also much better (Craig et al 1980). Hence distinguishing this histological subtype is important for surgical management and survival prognosis. This report describes a full radiological evaluation of such a case, covering the wide spectrum of relevant imaging modalities.     

Prolonged Complete Response after GEMOX Chemotherapy in a Patient with Advanced Fibrolamellar Hepatocellular Carcinoma

The only currently validated treatment for advanced hepatocellular carcinoma (HCC) is sorafenib. However, sorafenib has been mainly studied in patients with HCC developed in cirrhotic liver. Chemotherapy might be more suitable for patients with HCC in non-cirrhotic liver. We report the case of a young woman with fibrolamellar HCC in a non-cirrhotic liver, with histologically proven metastatic ganglionary relapse after surgical resection of the primary tumour. Chemotherapy with gemcitabine and oxaliplatin (GEMOX regimen) achieved a complete response without relapse five years after discontinuation of chemotherapy. This exceptional case raises the question of clinical trials specifically designed for patients with HCC in non-cirrhotic liver.Key words: Fibrolamellar hepatocellular carcinoma, Healthy liver, Oxaliplatin, Gemcitabine     

A light microscopic and ultrastructural study of two cases of fibrolamellar hepatocellular carcinoma

We describe two cases of fibrolamellar hepatocellular carcinoma of the liver in two young women. Both patients presented with diffuse intra-abdominal metastases; nevertheless they had a survival of 28 and 32 months, respectively, which sustains the better prognosis of this neoplasm. Electron microscopy of one case confirmed the oncocytic features of the neoplastic cells and showed intra- and intercellular duct-like vacuoles with numerous microvilli containing a microfilament core that terminated in a terminal web, which represents an unusual aspect in the spectrum of differentiation of fibrolamellar hepatocellular carcinoma.     

Multimodal treatment for adrenal metastases from hepatocellular carcinoma (HCC)

The patients with hepatocellular carcinoma (HCC) with adrenal metastases are often accompanied with the metastasis from other sites, and their prognosis is poor. After 1999, we examined the prognosis and efficacy of the seven patients with drenal metastases from HCC. Four patients were surgically treated, and three of them received radiation therapy (RT). All of the 7 patients were men and the mean age was 72 years old (range: 53-77 years old). The mean interval from the initial treatment of hepatocellular carcinoma to the adrenal metastases was 46 months (1-95 months). If there was a good control observed in the intrahepatic lesion with no metastases besides adrenal glands, we selected a surgical resection of the metastatic adrenal glands. The mean overall survival time after the surgical treatment of the adrenal metastases was 23 months (7-54 months), and we considered it as a good prognosis. The mean progression free survival of the adrenal metastases was 15 months (5-30 months). Besides on such a good clinical outcome, we conclude that aggressive multimodal therapy including surgical resection of metastatic foci may be recommended if the patients with hepatocellular carcinoma have no other metastatic sites other than the adrenal gland and liver lesions are well-controlled.     

The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients

Fibrolamellar hepatocellular carcinoma is a rare, malignant liver tumor that often arises in the otherwise normal liver of adolescents and young adults. Previous studies have focused on biomarkers and comparisons to traditional hepatocellular carcinoma, and have yielded little data on the underlying pathophysiology. We performed whole genome sequencing on paired tumor and normal samples from 10 patients to identify recurrent mutations and structural variations that could predispose to oncogenesis. There are relatively few coding, somatic mutations in this cancer, putting it on the low end of the mutational spectrum. Aside from a previously described heterozygous deletion on chromosome 19 that encodes for a functional, chimeric protein, there were no other recurrent structural variations that contribute to the tumor genotype. The lack of a second-hit mutation in the genomic landscape of fibrolamellar hepatocellular carcinoma makes the DNAJB1-PRKACA fusion protein the best target for diagnostic and therapeutic advancements. The mutations, altered pathways and structural variants that characterized fibrolamellar hepatocellular carcinoma were distinct from those in hepatocellular carcinoma, further defining it as a distinct carcinoma.     

Hépatocarcinome fibrolamellaire avec bourgeon endobiliaire : cas clinique

Fibrolamellar hepatocellular carcinoma (FHC), is a histological alternative of carcinoma hepatocellular (CHC). It is rare, especially associated to an endobiliary bud. It??s a young subject pathology, without any sex prevalence. It occurs apart from any hepatopathy. The etiology is unknown and there are no supporting factors. The alphafetoprotein (AFP) is normal. The magnetic resonance imaging (MRI) makes it possible to evoke the diagnosis confirmed by the anatomopathological examination. The treatment rests on the surgery: hepatectomy or liver transplantation. The forecast is good because of its resecability, the absence of a subjacent cirrhosis and young nature of the patients. We report the case of a 27 years old man who presents fibrolamellar hepatocellular carcinoma with endobiliary bud.     

Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation.

PURPOSE: Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS: The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS: Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION: In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.     

Fractional polynomials in a new metastatic renal carcinoma continuous prognostic index involving histology, laboratory, and clinical predictors

BACKGROUND: We analyzed the effect of histology and various clinical and laboratory predictors in a new continuous prognostic index for metastatic renal-cell carcinoma based on fractional polynomials. PATIENTS AND METHODS: We evaluated 322 metastatic renal-cell carcinoma patients treated with subcutaneous recombinant cytokine-based home therapies in consecutive trials. We evaluated papillary histology, along with age, disease localizations, C-reactive protein, and neutrophil count in a new prognostic index, which was based on the multivariable fractional polynomial (MFP) algorithm. RESULTS: The MFP model allowed us to divide patients into three risk groups, using seven selected significant prognostic factors: histology, neutrophils, C-reactive protein, bone metastases, liver metastases, lymph node metastases, and age. Using the multivariable fractional polynomial model, median overall survival for high-, intermediate-, and low-risk patients was 10 months (n=80), 23 months (n=162), and 41 months (n=80) (scheme A; p 相似文献   

Involvement of the central nervous system by ovarian carcinoma

Ovarian carcinoma rarely metastasizes to the central nervous system (CNS). Of 110 patients with epithelial ovarian carcinoma treated at the Northern Israel Oncology Center between the years 1979 and 1985, only five (4.5%) had CNS involvement. The median age of the patients with 54.5 years. All of them had treatment with cisplatin and Adriamycin (doxorubicin). The median duration from diagnosis to the development of brain involvement was 17 months. The median survival time was 28 months from diagnosis of carcinoma and 2 months from diagnosis of CNS disease. The increased incidence of this kind of metastasis in patients achieving local control of their advanced disease suggests that a change in the pattern of metastatic spread or the prolonged survival permits occult CNS metastases to become apparent. A routine computerized axial tomography (CAT) scan of the brain should therefore be performed on patients with ovarian carcinoma with prolonged survival.     

Pancreatic resection for metastatic tumors to the pancreas

BACKGROUND AND OBJECTIVES: The incidence of metastases to the pancreas is very low. The benefit of resection of pancreatic metastasis is poorly defined. In this review we evaluated the outcome of patients undergoing pancreatic resection for metastatic tumors to the pancreas. METHODS: Eight patients underwent pancreatic resection for metastatic tumor from December 1980 to June 2001. The primary cancer was colon carcinoma (n = 4), renal cell cancer (n = 2), duodenal leiomyosarcoma (n = 1), and malignant fibrous histiocytoma (n = 1). The median interval between primary treatment and detection of pancreatic metastases was 36 months. In two cases pancreatic metastases were synchronous with the primary tumor. RESULTS: Four patients underwent pancreatoduodenectomy, two distal pancreatectomy, one total pancreatectomy, and one median pancreatectomy. Associated resection of extrapancreatic lesions was performed in four patients, including two left hepatectomy and two left colectomy. There was no postoperative mortality, but two patients had a pancreatic and a biliary fistula, respectively. Survival averaged 23 months (range 14-42 months): four patients died for metastatic disease from 14 to 42 months after operation, while four patients are alive and well 14 to 31 months after surgery. CONCLUSIONS: Pancreatic resection for metastatic disease to the pancreas should be considered even in selected patients with limited extrapancreatic disease. Long-term survival or good palliation may be achieved.     

Hepatocellular carcinoma presenting with bone metastasis

Bone metastasis is an unusual complication of hepatocellular carcinoma. We report here 2 cases of patients with bone metastases of hepatocellular carcinoma at presentation. Patient No. 1 with liver cirrhosis and hepatocellular carcinoma was admitted with a bone metastasis in the rib. The patient was treated with hepatic arterial chemotherapy and rib resection. Patient No.2 was known to have an asymptomatic liver mass of uncertain histology for a year when he presented with back pain. Because of signs of spinal compression, laminectomy was performed, and the diagnosis of metastatic hepatocellular carcinoma was established. The presence of bone metastases in hepatocellular carcinoma at presentation is extremely rare. More frequently, bone lesions are observed after successful treatment of the primary liver tumor. Both surgery and radiotherapy are used as palliative treatment in bone metastases of hepatocellular carcinoma. The treatment of hepatocellular carcinoma presenting with bone metastasis by bone resection and intraarterial chemotherapy seems to be of limited impact on patient survival because of dissemination of micrometastases in other organs and the frequent presence of other comorbid conditions. However, effective palliation using this multimodality approach is feasible. Hepatocellular carcinoma should be considered in the differential diagnosis of bone metastases.     

Results of whole brain radiotherapy and recursive partitioning analysis in patients with brain metastases from renal cell carcinoma: a retrospective study

PURPOSE: To determine the benefit of whole brain radiotherapy (WBRT) and the use of the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification system in patients with brain metastases from renal cell carcinoma. METHODS AND MATERIALS: We identified 46 consecutive patients with brain metastases from renal cell carcinoma who were treated with WBRT at the Cleveland Clinic Foundation between 1983 and 2000. We reviewed their charts for patient and tumor characteristics and categorized them according to the RTOG RPA classes. RESULTS: The median follow-up and survival time for all 46 patients (15 women and 31 men) was 3.0 months. The median radiation dose was 3000 cGy in 10 fractions. Patients who received higher radiation doses (>3000 cGy) survived longer than those who received 3000 cGy or less than 3000 cGy (8.5 months vs. 2.7 months vs. 0.4 months, p = 0.0289). However, the Karnofsky performance status and RPA class were confounding factors in these data. The median survival for patients by RTOG RPA class was 8.5 months for Class I (n = 2), 3 months for Class II (n = 37), and 0.6 months for Class III (n = 7, p = 0.0834). CONCLUSION: Despite the relatively poor prognosis of patients who receive WBRT alone, it appears that they benefit from this palliative treatment. The RTOG RPA classification system may be a useful tool in assessing prognosis in this patient population.     

肝细胞肝癌脑转移临床特性和预后分析

目的：分析肝细胞肝癌（hepatocellular carcinoma,HCC）脑转移的临床特点和预后相关因素。方法：回顾性研究2004—0430—2011-12-01我院在放疗科诊治的32例HCC脑转移患者,其中27例接受脑部肿瘤的放射治疗,随访患者的生存情况。结果：32例患者中,27例患者出现中枢神经系统症状,5例无症状即发现颅脑转移。脑转移到死亡的中位生存期为（4．53±2．12）个月,颅脑HCC后到脑转移的中位时间为14．5个月,1年生存率为15．6％。单因素分析显示,颅脑症状（P=0．008）、RPA（P=0．002）、Child-Pugh肝功能分级（P〈0．01）及肝内病灶控制情况（P=0．040）与生存时间相关;多因素分析则显示,颅脑症状、颅内转移灶数目（P=0．027）和是否接受过脑转移灶放疗（P=0．001）是影响患者预后的主要因素。20例脑转移患者已经出现肺转移,21例患者死于肝内病灶未控,5例患者因脑转移灶未能控制而死亡。结论：HCC脑转移患者生存时间短,大部分患者以伴有颅外转移灶,颅内症状、肝功能分级、颅内病灶个数和是否放疗是预后主要因素。     

Hepatocellular carcinoma in young people

The clinical and pathologic features of 23 cases of hepatocellular carcinoma occurring in patients younger than age 35 years (mean age, 17.4 years) were analyzed. Ten of these (43%) were the fibrolamellar oncocytic variant (FLO), characterized by large polygonal neoplastic hepatocytes and lamellar bundles of collagen. The remainder (non-FLO) showed the usual wide range of gross and histologic patterns typical of hepatocellular carcinoma in older age groups. Overall, hepatocellular carcinoma was more common in females than in males. The FLO variant was characterized by a longer duration of symptoms prior to diagnosis, increased frequency of resectability of the tumor, and infrequency of mitoses. Of particular importance is the fact that 5 of 10 patients with the FLO variant are alive and clinically free of disease 1 1/2 to 8 years postoperatively, while none of the 13 patients with non-FLO hepatocellular carcinoma is alive and free of disease. There was no significant difference between the two groups in mean age at diagnosis, presence of single versus multiple hepatic tumors, vascular invasion, or tumor necrosis. Although cirrhosis was present in three non-FLO patients and none of the FLO patients, the difference was not statistically significant. The prognosis of hepatocellular carcinoma in young patients does not appear to differ from that in older patients, with the exception of the fibrolamellar oncocytic variant, a variant which is common in younger patients.     

Metastatic bone disease: a 36-year single centre trend-analysis of patients admitted to a tertiary orthopaedic surgical department

BACKGROUND AND OBJECTIVES: The treatment and outcome of primary malignant bone tumours has changed with the advances in diagnostic and treatment modalities. A trend-analysis on a large cohort of patients with metastatic bone disease was performed. METHODS: A retrospective chart review of all cases with metastatic bone disease admitted to a single tertiary orthopaedic referral centre, registered with the Vienna Bone and Soft Tissue Tumour Registry between 1968 and 2003 was conducted. For trend-analysis of frequency, survival, primary site, treatment methods, and others, the 36-year study duration was divided into four periods. RESULTS: The study identified 601 females and 580 males (mean: 60 years) with metastatic bone disease. The most common metastases were secondary to breast cancer (n = 275; 23%) and renal cell carcinoma (n = 242; 21%) and the majority were located in the femur (n = 332; 28%) and spine (n = 348; 29%). Overall, the proportion of patients who underwent surgery decreased. At follow-up, 887 (75%) patients were verified to have died of their disease. CONCLUSIONS: Over the 36-year period, the frequency of bone metastases has increased at our centre. Although survival increased over time, the difference was not significant; this was most likely attributable to the seriousness of cases referred to our tertiary care centre.     

Fibrolamellar hepatocellular carcinoma in Mexican patients

The aim of this report is to describe the frequency, clinical, and morphologic characteristics of fibrolamellar hepatocellular carcinoma in Mexican patients. Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma. Although this tumor appears to be predominant among the Caucasian population of the U.S, FLHCC has been described in many other countries. The frequency and characteristics of FLHCC in Latin American population is almost unknown. The clinico-pathologic characteristics of seven (5.8%) Mexican patients with FLHCC, obtained among 121 hepato-cellular carcinomas are described. The frequency of these tumors was compared with the frequency reported in other geographic areas in the international literature between 1980 and 1999. There were four women and three men. Two patients had taken oral contraceptives for six months and a year prior to diagnosis; another patient had positive serology for the hepatitis B virus. Common symptoms included a palpable mass, abdominal pain and weight loss; two patients presented jaundice. In two patients the tumor had been removed eight and three years previously, and they were readmitted when FLHCC recurred. In three patients the diagnosis was suspected in radiological studies (computed tomography and/or magnetic resonance). Laboratory tests were non-specific. In four patients, resection of the tumor was performed, and in the remaining three the neoplasm was diagnosed by percutaneous hepatic biopsy. Two patients had died of disease at the time of the study, and another was alive with recurrent disease. Conclusions: fibrolamellar hepatocarcinoma is an uncommon, but not an exceptional neoplasm in our population and represents 5.8% of all hepatocarcinomas reviewed.     

Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib

BackgroundThe aim of our study was to determine whether the presence of bone metastases affects outcomes in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) receiving sunitinib.Patients and methodsWe reviewed the charts of all patients in four academic centers in Belgium and France who started first-line sunitinib (50 mg/day; 4 weeks on and 2 weeks off) between January 2005 and December 2008. Data were collected on known prognostic factors for metastatic renal cell carcinoma and metastatic sites. Response and progression were evaluated by computed tomography scan (according to RECIST).ResultsTwo hundred twenty-three patients were identified. With a median follow-up of 40 months, median progression-free survival (PFS) and median overall survival (OS) were significantly shorter in patients with bone metastases than in those without: respectively, 8.2 versus 19.1 months (P < 0.0001) and 19.5 versus 38.5 months (P < 0.0001). On multivariate analysis, taking on account platelet count, Eastern Cooperative Oncology Group performance status, number of metastatic sites, neutrophil count, corrected serum calcium, time from diagnosis to systemic treatment, and the presence of bone metastases, bone metastasis was the independent variable most significantly associated with poor PFS (P < 0.0001) and OS (P = 0.001).ConclusionThe presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on outcome on sunitinib.     

乳头状肾细胞癌的临床治疗分析——附23例报告

目的总结分析乳头状肾细胞癌的临床特点,提高其治疗水平。方法回顾性分析1980～2000年收治的23例乳头状肾细胞癌患者的临床资料。男14例,女9例。中位年龄48岁（24～71岁）。左侧11例,右侧12例。在19例初治的患者中,临床表现血尿8例（42．1％）,腰痛7例（36．8％）,无症状者4例（21．1％）;肾脏肿瘤中位最大径5．5cm（2．5～10．0cm）。另4例为外院术后出现复发和转移。结果乳头状肾细胞癌占同期收治肾癌的2．4％（23／975）。失随访4例。术后总5年生存率69．6％。其中初治19例,5年生存率为84．2％。14例早期局限性癌（T1a～T2N0M0）患者5年生存率100％,但2例分别于术后7年6个月和10年出现转移,其中1例双肺转移患者行肺转移瘤切除和生物化疗后已生存9年且健在,1例失访。3例局部淋巴结转移和2例远处转移的患者中,1例术后2年6个月出现肺转移瘤和切口转移手术联合生物化疗后生存3年,1例同期肺转移瘤患者行肺转移瘤切除和放疗后生存6年,而余3例中,2例失访,1例生存6个月。而外院初治出现复发的4例中,2例患者再次行复发肿瘤切除,分别生存1年和2年6个月,另2例转移患者中,1例生存9个月,1例失访。结论乳头状肾细胞癌在国内少见。早期局限性乳头状肾细胞癌术后预后良好。对于复发或转移的乳头状肾细胞癌患者,手术切除转移瘤或复发瘤可提高生存期。     

Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study

Combined hepatocellular-cholangiocarcinoma is a rare form of primary liver cancer showing features of both hepatocellular and biliary epithelial differentiation. In a review of 24 cases of this tumor, three histologic types were encountered. Four cases were Type I or "collision tumors," apparently a coincidental occurrence of both hepatocellular carcinoma and cholangiocarcinoma in the same patient. Twelve cases were Type II or "transitional tumors," in which there were areas of intermediate differentiation and an identifiable transition between hepatocellular carcinoma and cholangiocarcinoma. Eight cases were Type III or "fibrolamellar tumors" which resembled the fibrolamellar variant of hepatocellular carcinoma but which also contained mucin-producing pseudoglands. Type III tumors differ from other combined tumors, occurring at a younger age, in the absence of cirrhosis, and having a slightly longer survival. Immunohistochemical (immunoperoxidase) staining for intracellular antigens showed that alpha-fetoprotein is a fairly specific, although insensitive, marker of hepatocellular differentiation in primary liver cancers, being present in 50% of typical hepatocellular carcinomas and in hepatocellular areas in 29% of combined tumors, but in no cholangiocarcinomas or cholangiocellular areas of combined tumors. Keratin is a good marker of biliary epithelial differentiation, being found in 90% of cholangiocarcinomas and in 52% of combined hepatocellular cholangiocarcinomas, but in no hepatocellular carcinomas. Alpha-1-antitrypsin, fibrinogen, IgG, and carcinoembryonic antigen may be found in both hepatocellular carcinoma, cholangiocarcinoma, and in combined tumors; these antigens are therefore of limited use in differential diagnosis.