Teratoid Wilms' tumor

A child with bilateral Wilms' tumors is reported. The left renal tumor showed nephroblastoma with several tissues of apparent mesenchymal derivation and tubules with diverse epithelial differentiation. The right-sided tumor showed the more familiar triphasic pattern of nephroblastoma. Initial percutaneous renal biopsy of the left tumor did not reveal nephroblastoma but showed tubules with various epithelia and mesenchymal elements, and led to a diagnosis of teratoma. The pathogenesis of this complex neoplasm is discussed, and argument is presented that primitive renal blastema may be capable of more diverse differentiation than has previously been realized. A comparison is drawn between this neoplasm and some cases of hepatoblastoma. Certain cases reported as renal teratoma may be similar in nature.     

Autoradiographic analysis of proliferative activity in rat kidney epithelial and mesenchymal cell subpopulations following a carcinogenic dose of dimethylnitrosamine.

In a system that yields 100% incidence of renal mesenchymal tumors and a 30 to 40% incidence of renal cortical epithelial neoplasms, the proliferative activity of renal epithelial and mesenchymal cell subpopulations following a single dose of dimethylnitrosamine (DMN) was traced by autoradiographic analysis of [methyl-3H]thymidine uptake during the 3 weeks immediately posttreatment. The initial response to DMN was a depression in DNA synthesis and mitosis to near 0 levels in all segments of the nephron and in attendant mesenchymal cells for a period of 1 to 3 days. Following the period of inhibition, increased DNA synthetic activity was observed in certain subpopulations of both epithelium and mesenchyme and these patterns were matched by equivalent mitotic activity. A stimulation of DNA synthesis was observed in cells of the proximal and distal tubules of Zones 1 and 2 but in no other epithelial segments. The increased activity was most intense in Zone 1 epithelium reaching a peak at the 10th day after DMN injection 4 days after epithelial cell necrosis had commenced. In renal mesenchyme, the major response involved only the interstitial cells of Zones 1 and 2. At Day 3, there was a wave of increased DNA-synthetic and mitotic activity in the free interstitial cells of the cortex, followed by a 2nd, more intense peak of activity at Day 6. The cells responding at Day 3 appeared to involve the resident population of cortical fibrocytes while the major contribution to the Day 6 peak came from infiltrating mononuclear inflammatory cells, although resident fibrocytes and capillary endothelium also contributed. A significant wave of increased activity involved the intestitial cells of Zone 2, but the peak, although of equivalent intensity to the response in Zone 1, was single and occurred 3 days later at Day 9. Apart from a small, brief, and variable wave of activity in interstitial cells of Zone 3 from Days 8 to 10, no toerh mesenchymal cell populations in the kidney were stimulated by the injection of DMN.     

Morphological and immunohistochemical studies of the estrogen-induced Syrian hamster renal tumor: probable cell of origin

Chronic natural or synthetic estrogen treatment of Syrian golden hamsters leads to the development of malignant renal neoplasms. In the present study, morphological and immunohistochemical studies were performed to further characterize the estrogen-induced hamster renal tumors. The neoplasms were composed of two distinct cell populations: a large-cell component that appeared highly epithelial, and a poorly differentiated small-cell component. Importantly, both cell types had epithelial characteristics, since they contained desmosomes at their cell surfaces. However, the large-cell component possessed additional epithelial features such as microvilli, intracytoplasmic lumens, and cilia. Comparative studies of renal tumors and developing renal tissue from fetal and newborn hamsters revealed remarkable histological similarities. Morphologically, the large tumor cells resembled early metanephric tubules and the small tumor cells were very similar to the blastemal cells of the developing kidney. The earliest tumor foci were found after 4.5 months of treatment. They were consistently found in the kidney interstitium in proximity to large arteries. Immunohistochemical staining for intermediate filaments in developing fetal and newborn kidneys demonstrated cytokeratin in renal tubules, desmin in blastemal cells, and vimentin in stromal cells. Estrogen-induced renal tumor cells uniquely possessed reactivity for all three intermediate filaments, clearly demonstrating their epithelial and mesenchymal characteristics. Based on their morphological resemblance to developing embryonic kidney cells and the presence of both epithelial and mesenchymal intermediate filaments, our findings provide strong evidence that the cell of origin of this malignant tumor is a precursor cell that is committed to an epithelial differentiation pathway.     

Production of epithelial and mesenchymal tumours with rat liver cells transformed in vitro.

Epithelial-like cells originating from the livers of 10-day and 8-week-old BD rats were established in culture. The cells were treated in vitro for 1 or 4 weeks with dimethylnitrosamine (DMN) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Although some structural changes were observed in treated cells, it was not possible to score for morphological transformation in vitro. Newborn syngeneic rats were injected with 1.5-2 times 10(6) treated or 1.5-5 times 10(6) control cells at various times up to 38 weeks from the beginning of treatment with the carcinogen. Following the injection of DMN-treated cells, a total of 32 of the 42 injected rat developed tumours, of which 17 were epithelial, 10 carcinosarcomas and 5 fibrosarcomas. Following the injection of the MNNG-treated cells into 61 rats, a total of 30 tumours were observed, including 8 carcinomas, 9 carcinosarcomas and 13 fibroscarcomas. Tumours, mainly of the mesenchymal type, were also observed in rats inoculated with control cells but at a lower frequency. The observation observed in rats inoculated with control cells but at a lower frequency. The observation of mesenchymal tumours is attributed to the presence of a mixed population of epithelial and mesenchymal cells in the orginal culture.     

An ultrastructural study of mixed hepatoblastoma with osteoid elements.

A case of mixed hepatoblastoma with osteoid elements was studied by light and electron microscopy. The ultrastructure of the epithelial elements showed a lack of differentiation and simple cytoplasmic organelles. However, an occasional cytoplasmic crystalloid structure were seen. The ultrastructure of the osteoid foci showed fibroblast-like cells capable of collagen formation, clearly distinguishable from the epithelial elements. These cells had neoplastic characteristics of nuclear pleomorphism and high nucleo-cytoplasmic ratio. These findings support the belief that hepatoblastoma arises from a multipotential blastema capable of both epithelial and mesenchymal differentiation, with the osteoid elements being an intrinsic neoplastic component of the tumor.     

Liver tumours

Primary hepatic tumours in children represent an heterogeneous group of neoplasms. Malignant tumours are more common (60% of primary liver tumours), but account for only 1.2–5% of all paediatric neoplasms. There are two main types of malignant tumour, those of epithelial origin, hepatoblastoma (HB) and hepatocellular carcinoma (HCC), and the rarer mesenchymal tumours, e.g. rhabdomyosarcoma and undifferentiated sarcoma, (Weinberg AG, Finegold, MJ. Primary hepatic tumours of childhood. Hum Pathol 1983, 14, 512–532[1]). Vascular tumours e.g. haemangioendotheliomas are the most common of the benign tumours followed by mesenchymal hamartoma and the rare hepatic adenoma and focal nodular hyperplasia. This article will concentrate on the malignant epithelial tumours.     

Selective suppression of metastasis but not tumorigenicity of a mouse lung carcinoma by cell hybridization

Somatic cell hybrids were produced by polyethylene glycol-induced cell fusion between metastatic CMT 167 (HGPRT-/OUAR) C57BL/Icrfat mouse lung carcinoma cells and 2 non-metastatic cell lines: C3H/He mouse L-M(TK-) cells of mesenchymal origin and EJ (OUAS) human bladder carcinoma cells. Fusion of 2 different CMT167 (HGPRT-) clones with L-M(TK-) cells followed by selection in HMT medium gave rise to 14 intraspecific hybrids, which were shown to express H-2 antigens specific for both the C57 and C3H mouse strains. Three interspecific hybrids arising from fusion of EJ(OUAS) and CMT167(HGPRT-/OUAR) cells were selected in HMT/ouabain medium and characterized by human isozyme analysis. All the hybrids produced large tumours after subcutaneous inoculation of 5 X 10(5) cells into adult athymic nu/nu mice. The intraspecific hybrid tumours were predominantly sarcomatous (mesenchymal) in structure but a few contained epithelial acini. Metastatic ability (as assessed by production of lung metastases) was completely suppressed in 13 of the 14 mouse/mouse hybrid cell clones. These results suggest that tumorigenicity, tumour structure and the ability to metastasize are expressed independently. The interspecific hybrids, which had not retained a full human chromosome complement, produced metastatic tumours that remained epithelial in structure.     

Cytotoxicity of cyclophosphamide in the rat incisor.

Three of the 4 groups of 3 Wistar rats each were given 40 mg, 80 mg and 120 mg cyclophosphamide/kg respectively by single intraperitoneal injections. The fourth group was given 2 ml of normal saline as control. One animal from each group was killed after 1, 4 and 8 days. The incisor teeth of all experimental animals showed evidence of cytotoxic injury, which appeared to be more severe with increasing dosage, to the undifferentiated mesenchymal cells in the proliferating zone of the pulp close to the basal odontogenic epithelium, cessation of root growth and relative acellularity of the basal area of the pulp. Evidence of cytotoxicity to the odontogenic epithelium was seen only in the groups given 80 mg/kg and 120 mg/kg. Resolution of the cytotoxic injury and re-establishment of normal basal odontogenesis were seen in the 40 mg dose group by the eighth day but appeared to be slower with increasing dosage. It would seem that of the rapidly proliferating epithelial and mesenchymal odontogenic cells in the basal area of the rat incisor those in the mesenchyme may be most susceptible to the cytotoxicity of cyclophosphamide. The odontogenic epithelium may be resistant to the cytotoxicity of 40 mg cyclophosphamide/kg. The results may be of significance in the investigation of the mechanism of cytotoxicity of this cancer chemotherapeutic agent.     

Mixed mesodermal tumor of the ovary

A 68-year-old woman with a malignant mixed mesodermal tumor of the ovary is reported. Her clinical course worsened rapidly and she died 3 months after admission. At autopsy, the pelvic cavity was seen to be filled with a huge tumor mass. Histologically, the tumor contained malignant epithelial and mesenchymal elements. The epithelial component was an adenosquamous carcinoma. The stromal element was comprised mainly of anaplastic, undifferentiated spindle cells. A variety of malignant mesenchymal elements were also present. They resembled rhabdomyosarcoma, liposarcoma, chondrosarcoma, fibrosarcoma, and myxosarcoma . A review of the Japanese literature concerning this tumor is also presented.     

Intercellular junctions of methylcholanthrene-induced rat skin basocellular and squamous carcinomas.

The occurrence of different intercellular junctions in epithelial rat skin tumours induced by methylcholanthrene was investigated using thin sections and freeze-fracture replicas examined by electron microscopy. Tumours which appeared first were basal cell carcinomas. Later, different tumours of hair follicle and of sebaceous gland origin were formed. Finally, in the majority of tumours a squamous component evolved. Metastases developed from the squamous carcinomas exclusively. Desmosomes and gap junctions were detected in basal cell carcinomas whereas, in squamous carcinomas, tight junctions were also seen. While all three types of junction were found in the primary squamous tumours, the tumour metastases in lymph nodes and lungs contained only desmosomes.     

Localized primary tumors of the pleura: an analysis of 40 cases.

A study of 40 localized primary tumors of the pleura in the files of the Canadian Tumour Reference Centre revealed a considerable diversity in their histologic structure. Collagenized, hemangiopericytoma-like and cellular areas were the main forms of growth pattern, with half of the tumors showing a mixture of two or more of these elements. Inclusions of non-neoplastic bronchioloalveolar epithelium were frequently seen in areas of tumor adjacent to lung substance but in only one tumor was there a neoplastic component of epithelial form. Eight tumors (20%) showed evidence of malignant behavior. All of these were large and cellular at the time of initial surgery and four had mitotic counts of 10 or more/10 H.P.F. in areas. The evidence suggests that the great majority of localized pleural tumors arise from submesothelial mesenchymal elements and it is believed that the term mesothelioma should not be used in reference to these growths.     

Smooth-muscle-associated contractile protein in renal mesenchymal tumour cells and in transformed cells from DMN-injected rats.

Cryostat sections and established in vitro cultures of dimethylnitrosamine(DMN)-induced renal mesenchymal tumours and monolayer cultures of transformed kidney cells derived from rats treated with a carcinogenic dose of DMN were examined by indirect immunofluorescence with human serum containing smooth muscle antibody. Eight mesenchymal tumours examined showed filamentous cytoplasmic staining of spindle cells infiltrating between renal tubules, whilst in normal kidneys interstitial cells were only weakly positive. In established in vitro cultures from 6 mesenchymal tumours, different patterns of staining were observed in morphologically different cell forms, ranging from fine filamentous staining in giant cells to diffuse cytoplasmic fluorescence in small bipolar cells, and cell outline staining in polygonal cells. In addition filamentous staining of microvillous projections and nucleolar staining were observed in some tumour cells. Monolayer cultures of transformed kidney cells showed strong staining of coarse, randomly-orientated cytoplasmic filaments, whilst fibroblasts cultured from normal rat kidney demonstrated an ordered array of fine, parallel filaments. Specificity of the immunofluorescent staining reaction was established by failure to obtain staining with normal serum, with smooth muscle antibody serum neutralized by homogenates of smooth muscle or extracts containing actin derived from smooth muscle. These results indicate that there is an apparent increase of actin-like contractile microfilaments in transformed cells and in renal mesenchymal tumours. The cytoplasmic contracile microfilaments in these cells may play a role in tumour cell mobility and invasion.     

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities

Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specific role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.     

Immunocytochemical study of an endometrial diffuse clear cell stromal sarcoma and other endometrial stromal sarcomas

Intermediate filament composition was studied in the following endometrial stromal tumors: low-grade stromal sarcoma (endolymphatic stromal myosis), high-grade stromal sarcoma with an associated adenocarcinoma (collision tumor), diffuse clear cell stromal sarcoma and a mesodermal mixed tumor (carcinosarcoma). The tumor cells of the stromal tumors as well as the mesenchymal elements of the mixed mesodermal tumor were decorated exclusively with antibodies to vimentin. Desmin was not demonstrated in these tumor cells. A biochemical study of the cytoskeletal filaments present in the low-grade stromal sarcoma revealed, in addition to vimentin, beta and gamma actin as seen in normal endometrial stroma. Cytokeratins were only identified in epithelial components which were present in some of these tumors. Intermediate filament typing in these endometrial neoplasms contributes to the elucidation of histogenetic problems, may delineate mesenchymal from epithelial elements, may separate muscle from stromal lesions and in one instance helped to define a hitherto unreported diffuse clear cell stromal sarcoma.     

The histogenesis of tumours induced in golden hamsters by murine sarcoma virus-Harvey (MSV-H)

Newborn golden hamsters were inoculated subcutaneously with a cell-free filtrate of cultured mouse 3T3 cells infected with murine sarcoma virus-Harvey (MSV-H). An electron microscopical study was made of the lesions that subsequently developed in these hamsters. Two weeks after inoculation, cysts developed eccentrically in the hila of lymph nodes draining the inoculation site. Type H (radial) virus-like particles were seen in the endothelial cells that lined the cysts and in the serous fluid that filled the cysts. During the 3–6 weeks after inoculation, nodules appeared in lymph nodes, subcutaneous and muscle fascia. They were composed of pleomorphic cells that interlocked with each other and resembled the fixed phagocytic histiocytes of normal lymph nodes. The pleomorphic interlocking cells infiltrated and replaced lymph nodes and perinodal tissues. Some lymph nodes were replaced by abnormal mast cells. During the 12–24 weeks after inoculation tumours were found that involved the paws or limb muscles. The predominant cells in these tumours were similar to the pleomorphic interlocking cells seen in early developing lesions. Similar cells were also found in lymph nodes draining the tumours. It is concluded that tumours induced in golden hamsters by MSV-H are mesenchymal tumours of histiocytic origin.     

The significance of atypia within teratomatous metastases after chemotherapy for malignant germ cell tumors

The completely resected teratomatous metastases of 55 patients who had been treated with cisplatin-based combination chemotherapy for non-seminomatous germ cell tumors were reviewed to see if cellular atypia had an effect with respect to recurrent disease. The degree of atypia of the epithelial and mesenchymal elements was assessed on the basis of the cytologic features and mitotic activity. Twenty-three percent of the cases contained high-grade epithelial elements, whereas high-grade mesenchymal elements occurred in 18% of the cases; in addition there were nine cases classified as showing frankly malignant teratomatous elements. The presence of cytologically disturbing epithelial and mesenchymal elements (which, however, lacked an invasive malignant pattern) correlated with an increased incidence of recurrent teratoma compared to less atypical teratomatous elements (23% vs. 6% for epithelial elements, and 18% vs. 9% for mesenchymal elements, respectively). This difference, however, was not statistically significant (P greater than 0.05). There was no correlation between teratomatous atypia and recurrent, non-teratomatous germ cell tumor. The presence of an invasive malignant pattern did identify patients at significantly increased risk for recurrent teratoma-derived tumor. The authors conclude that cytologic atypia in the absence of invasion is not sufficient justification for altering the usual therapeutic strategies for patients with teratomatous metastases.     

Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component

Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died 8 weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor.