Spindle cell tumors resected from male patients with germ cell tumors. A clinicopathologic study of 14 cases.

We identified 14 male germ cell tumor patients (13 of whom had received prior chemotherapy) in whom distinctive neoplasms composed of spindle to stellate cells set in a myxoid to collagenous stroma containing numerous blood vessels developed. These neoplasms were cytokeratin-positive and vimentin-positive and alpha-fetoprotein (AFP)-negative. Ten patients with neoplasms of low cellularity and no mitoses have not had tumor recurrences, whereas four patients with more cellular and mitotically active tumors have experienced either recurrences or death. We recommend simple surgical excision, without additional chemotherapy, for the hypocellular, mitotically inactive cases. The transition from mitotically active spindle cell tumors to frankly sarcomatous areas in three cases indicates that these lesions may be the substratum for the development of sarcomas in some patients with germ cell tumors. Based on their histologic appearance and immunohistochemical profile, as well as preceding evidence of yolk sac tumor (YST) in 11 patients (data incomplete in 3 cases), we speculate that many of these cases represent overgrowth of a spindle cell component of YST that is selected for by chemotherapy.     

Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression.

Line 1 and line 10 tumors became invested in a fibrin-gel cocoon within hours after transplantation to the subcutaneous spaces of unsensitized syngeneic inbred Sewall Wright strain 2 guinea pigs. The fibrin gel comprised more than 80% of the line 1 tumor mass and, after day 3, became organized and was subsequently replaced by fibrous connective tissue, which gave the tumor the appearance of a scirrhous carcinoma. A cellular infiltrate of lymphocytes and basophils developed at the periphery of line 1 tumors after day 8, and tumors regressed by day 13. The fibrin gel investing the highly malignant line 10 tumors accounted for less than 10% of the tumor mass and persisted without fibrous organization as a tumor grew progressively and invaded adjacent tissues. These data provide new and potentially important insights into the biology of solid tumor growth and the mechanisms of immunologic tumor rejection. Envelopment of tumors in a fibrin gel created an anatomic barrier separating the tumors from the host. Neovascularization mimicking that about line 1 and line 10 tumors was induced by sc fibrin implants; these data suggest that activation of the clotting and/or fibrinolytic systems by tumor cells may itself provide sufficient stimulus for induction of tumor angiogenesis without requiring a separate tumor angiogenesis factor. The scirrhous pattern of growth characteristic of line 1 tumors apparently was achieved by organization of an abundant fibrin gel. Line 1 tumor regression did not for the most part involve direct contacts between tumor cells and any type of inflammatory cell, including macrophages; rather, tumor destruction was effected by ischemic necrosis secondary to widespread microvascular injury. The mechanisms of such injury are uncertain, but tumor rejection was correlated with evidence of developing cellular immunity and anatomic associations between lymphocytes and myofibroblasts. Further experiments will be necessary before these findings can be generalized to other tumor systems.     

Chemically induced differentiation of murine embryonal carcinoma in vivo: transplantation of differentiated tumors

Murine embryonal carcinoma tumors were induced to differentiate in vivo by administration of retinoic acid. Six long-term surviving animals had seven slowly growing tumors which were transplanted s.c. into strain 129 mice. Untreated embryonal carcinomas were transplanted as controls. All of the 16 control transplants grew rapidly and killed their hosts within 25 days. All of the 24 transplants of retinoic acid-differentiated tumor survived. Sixteen experimental transplants originating from five original tumors showed no or slow growth for up to 16 weeks and were found to be histologically benign cystic teratomas. Two original tumors gave rise to eight relatively rapidly growing transplants. One tumor resulted in four histologically similar solid tumors which resembled chondrosarcomas, and the second tumor gave rise to four histologically similar solid tumors which proved to be a mixture of glioma and chondrosarcoma. Examination of the tumor sources of these latter transplants showed benign cystic teratomas with focal solid, mitotically active cellular areas which were histologically similar to the transplants. These data confirm that retinoic acid-induced differentiation of murine embryonal carcinoma cells results in altered biological potential of these cells and usually the formation of a benign teratoma. Rarely (about 1 per 2 X 10(8], the resulting differentiated cells will give rise to rapidly growing, histologically malignant tumors. One can predict such biological propensity when solid, mitotically active areas in the original tumor are found.     

Nonepithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx. A clinicopathologic study. XIV: Chordomas

Twenty cases of a rare tumor, chordoma involving the nasal cavity, paranasal sinuses, or nasopharynx, are reported. Patients most often had localized headache, nasal obstruction, decreased hearing, or symptoms related to cranial nerve involvement, especially diplopia. A mass bulging into the nasopharynx, posterior nasal cavity, or pharynx was found on physical examination in 13 of these 20 patients, and in another 6 patients on radiologic examination. Paralysis of one or more cranial nerves was identified in the majority of patients who had tumors involving the upper nasopharynx. On radiologic examination, bone destruction was frequently identified in the clivus and sphenoid areas, and less commonly in the cervical vertebrae. Each patient had biopsy-proven tumor in the nasopharynx or sphenoid areas. Patients usually were treated by combinations of surgery and radiotherapy, in some cases leading to prolonged periods of apparent tumor control. Radiotherapy frequently resulted in regression of symptoms, sometimes lasting many months or years. A few tumors that involved mainly the lower nasopharynx were more amenable to surgical resection, in one case leading to apparent tumor control. In those cases with adequate follow-up information, most patients had either died of their disease or were living with recurrent or persistent inoperable tumor. Some patients lived for many months or years between recurrences or with known tumor, indicating that chordomas often are slowly growing neoplasms. The histologic features of these chordomas are described and illustrated, and the histopathologic differential diagnosis is discussed.     

Expression and activity of MMPS and their regulators in ovarian cancer

In order to understand the ability of human ovarian cancers to degrade the basement membrane, we have studied the localization and activity of matrix metalloproteases (MMPs) 2 and 9, using in situ hybridization and quantificative zymography on sequential sections of tumor biopsies. We have related these data to expression of some of the controlling elements of the enzymes, namely tissue inhibitors of metastasis (TIMPs) and tumor necrosis factor (TNF). mRNA for MMP-2 was found in the majority of cases and localized to stromal areas with maximal expression adjacent to neoplastic areas. MMP-9 expression was associated with cells in epithelial and stromal areas, consistent with distribution of macrophages. Zymography revealed higher levels of MMP-9 activity in the ovarian cancer biopsy samples than in other cancers studied, but in contrast to our previous observations in breast and bladder cancer, there was no correlation between MMP levels and tumor grade. Nor was there any association between amount of TNF mRNA and levels of MMP enzymes. TIMP-I expression was localized to stromal areas adjacent to tumor epithelial cells as well as, in some cases, to epithelial cells. The pattern of TIMP-2 expression wax similar to that of MMP-2. We conclude that the stromal elements of ovarian tumors express MMP-2 and 9 and their specific inhibitors, but these do not seem to be controlled by endogenous TNF in the tumor microenvironment. © 1994 Wiley-Liss, Inc.     

Participation of alpha-smooth muscle actin-positive cells in renomedullary interstitial cell tumors

Renomedullary interstitial cell tumors are benign lesions which are generally discovered in specimens nephrectomized for other malignant tumors or by autopsy. We examined the histologic features of eight tumors from four patients and investigated the appearance of alpha-smooth muscle actin (ASMA)-positive cells in these tumors using immunohistochemistry. We considered that five tumors are cellular type and the remaining three as fibrous. Characteristic hyalinization was observed in two of the three fibrous tumors. All the tumors except for one fibrous type contained entrapped tubular cells. CD35-positive cells (dendritic cells) and ASMA-positive cells were observed in all the tumors, with a more frequent occurrence in the cellular type than the fibrous type. CD35-negative spindle cells were considered as fibroblasts or activated fibroblasts (myofibroblasts). The number of CD35-positive cells was higher than that of ASMA-positive cells. Additionally, the entrapped tubular cells showed the transition to spindle cells and some of them expressed for ASMA. With double immunohistochemical staining, there were some cells showing positive reactions for both CD35 and ASMA. Furthermore, an ultrastructural examination confirmed the presence of ASMA-positive filaments in the dendritic cells and myofibroblasts. The expression of TGF-beta 1 was observed not only in the tumor cells and the collecting ducts surrounding the tumor but also in the entrapped tubular cells. In addition, the intensity of TGF-beta 1 was stronger in/around the tumor than in the areas distant from the tumor. The positive cells were more numerous in the cellular type than in the fibrous type. In conclusion, ASMA-positive cells appear in renomedullary interstitial cell tumors and some of the cells may originate in dendritic interstitial cells, fibroblasts including myofibroblasts, and entrapped tubular cells. Furthermore, TGF-beta 1 may contribute to the formation of fibrosis in the tumors.     

Chondroma of soft parts.

The clinical and pathological features of 104 cases of chondroma of soft parts are presented. The tumor occurred predominately in the third and fourth decades, was slightly more common in male (61%) than in female patients, and affected chiefly the soft tissues of the hand (64%) and feet (20%). The presenting symptom was usually a slowly and insidiously growing mass, occasionally causing tenderness or pain. Nearly always the tumor was well demarcated and lobulated and measured between 1 and 2 cm in greatest diameter. Microscopically, most of the tumors were composed of adult-type hyaline cartilage, undergoing calcification in a large percentage of cases. In addition, histologic variants with giant cell proliferation and chondroblastic activity could be distinguished. Despite the slight cellular pleomorphism and the plump appearance of many cartilage cells in the chondroblastic variants, there was no evidence that these tumors behaved differently from the tumors composed predominately of adult-type hyaline cartilage. Of the 56 patients with follow-up information (median follow-up period, 5.7 years) 44 were alive and well with no evidence of recurrence in the follow-up period. In 10 patients the tumor had recurred once. Multiple recurrences or metastatic lesions were no observed. Two patients died of unrelated cause. Complete local excision appears to be the treatment of choice.     

Cellular retinol-binding proteins in head and neck tumors and their adjacent tissues

The levels of cellular retinol-binding protein (CRBP) were examined by Scatchard analysis in 17 surgically resected human head and neck tumors and their adjacent normal tissues (normal tissues corresponded to muscle tissue). The center area and the marginal area of tumors were tested for their levels of CRBP in 17 cases, and the adjacent tissue was tested in 13 of the 17 cases. Only a small difference (if any) in the dissociation constant (Kd values) was seen in some cases between tumor and adjacent tissue; in most cases the Kd values in both areas were similar, and these values were also similar between the central and marginal areas of tumors. The average level of CRBP in the marginal area of the tumors was higher than that in the center area of the tumors in all the 17 cases. Among the 13 tumor cases whose adjacent tissues were tested, 12 showed CRBP levels more than two times higher in the marginal area of tumors; whereas in only one case was the level in the marginal or the center area of tumor similar to that in the adjacent tissues.     

Heterogeneity of heat response in murine, canine and human tumors: influence on predictive assays

The heterogeneity of response to hyperthermia of cells taken from different regions of tumors was tested in a model tumor system (RIF-1) in the mouse and in specimens from spontaneous tumors taken from dogs and humans at the time of surgical resection. Cell survival was assayed by clonogenic survival in the murine tumor and by dansyl lysine staining in tumors from all three species. Using survival as an endpoint, it was found that the extent of heterogeneity depended on the temperature to which the tumor was heated and the duration of exposure. By increasing either of these factors, the coefficient of variation was increased. The large heterogeneity seen after in vivo heating could not be explained entirely by inhomogeneous heating within the tumor as evidenced by temperature mapping. It is concluded that other microenvironmental factors such as blood flow, pH, O2, and nutrient supply may cause variations in the heat response of the tumor cells in vivo. Little, if any, evidence of cellular heterogeneity was evident for all three species when comparisons were made between samples of 100-200 mg. The canine and human tumors were considerably more heat resistant when dansyl lysine was used as an endpoint. In the RIF-1 tumors, heterogeneity of heat response was greater after in vitro heating than after in vivo heating when small biopsy samples (10-20 mg) were taken, suggesting that some cellular heterogeneity was present.     

Adenocarcinoid tumor of appendix presenting as unilateral Krukenberg tumor

We report a case of adenocarcinoid tumor of the appendix that presented initially as a unilateral Krukenberg tumor (a signet ring cell mucinous adenocarcinoma with prominent cellular stroma). The primary tumor in the appendix was discovered 10 months later at the time of a "second look" laparotomy. The ovarian metastasis showed both goblet cell elements and tubular formations with numerous argyrophilic cells, indicating that both components of these tumors may metastasize, a finding at variance with the conclusions of some authors who suggest that only the mucinous component may metastasize. Theories of histogenesis of these tumors are discussed, and 12 previously reported cases presenting as Krukenberg tumors (all bilateral) are reviewed. Because the primary tumor in the appendix may be small and easily missed, appendectomy is recommended in all patients with Krukenberg tumors when another primary site cannot be identified at the time of surgery.     

Detection by in situ hybridization of messenger RNAs of collagen types I and IV in murine mammary cancer

Ten breast carcinomas developing in C3H/Bi female mice were studied by an in situ hybridization technique using cDNA probes encoding alpha-I chains of collagens of types I and IV. The results obtained are compared to histochemical data on antibodies to collagens of types I and IV and ultrastructural observations on these tumors. Immunohistochemistry has revealed the presence of type-IV collagen in basement membranes lining intraductal and well-differentiated cancer nests. Type-I collagen was detected in the stroma surrounding these cells. There was no cellular labelling when these antisera were used. In situ hybridization has shown that type-IV collagen mRNA is detected in non-invasive intraductal and well-differentiated tumor cells and in endothelial cells in the stroma. Good correlation between detection of type-IV collagen lining these cells and evidence of mRNA by in situ hybridization was thus observed. Invasive cancer cells did not express hybridization grains with the type-IV collagen probe. Type-I collagen mRNA was visualized in stromal cells, probably fibroblasts and myofibroblasts as shown by electron microscopy. The most active cells were localized close to non-invasive areas. Our data indicate persistent in-vivo biosynthesis of type-IV collagen by some cancer cells that produce their own limitative environment; they suggest that type-IV collagen is not produced by invasive tumor cells and that stromal cells lining the non-invasive regions have a peculiar behavior.     

Relationship between in utero development of the mouse liver and tumor development following transplacental exposure to ethylnitrosourea

Pregnant C3HeB/FeJ mice were treated with ethylnitrosourea (ENU) on one of gestation Days 10, 13, or 15 to determine if ENU treatment at different stages of gestation would result in morphological or quantitative differences in liver tumors induced in the offspring. Liver tumors were counted and measured 6 mo after treatment with ENU. Foci of cellular alteration were identified histologically and counted. Liver tumor number and foci of cellular alteration increased as a function of increasing dose and age at the time of ENU treatment. An inverse relationship between age at the time of treatment and the size of liver tumors was found. The mean tumor volume of male mice exposed on Day 10 of gestation was 123-fold larger than for spontaneous tumors observed in controls. The differences between mean liver tumor volume in mice which had been exposed to ENU on Days 10, 13, or 15 of gestation appeared to be associated with the exponential growth of the fetus during this period of gestation. Unique, large, multinodular foci of cellular alteration were found in mice treated on Day 10 of gestation. The relationship between the stage of gestation and the size of chemically induced liver tumors in these mice is similar to previous observations with transplacentally induced lung tumors in C3HeB/FeJ mice. This indicates that developmentally regulated cell proliferation occurring at the time of carcinogen exposure may affect the subsequent extent of tumor development in both the liver and lung. Therefore, cells transformed during early development may result in tumors that pose a greater biological hazard than those transformed in later development.     

Use of macrophages to target therapeutic adenovirus to human prostate tumors

New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells.     

卵巢富细胞纤维瘤24例临床病理分析

  目的  探讨卵巢富细胞纤维瘤的临床与病理学特征。  方法  收集2008年2月至2017年3月复旦大学附属妇产科医院诊治的24例卵巢富细胞纤维瘤患者的临床病理资料，观察肿瘤组织学特征、免疫表型，并进行随访。  结果  24例患者年龄为17~70岁，平均46.5岁。临床症状包括卵巢肿块、下腹胀痛或合并胸腹水。2例患者术前伴CA125显著升高。卵巢富细胞纤维瘤发生于右侧卵巢、左侧卵巢、双侧卵巢分别为13、10、1例。镜下显示肿瘤细胞丰富、无明显异型性。3例患者的肿瘤细胞核分裂象活跃，核分裂象5~7个/10个高倍视野（high power fields，HPF），3例患者的肿瘤中含少量（少于10%）性索成分，4例见黄素化细胞。随访1~109个月，未见复发。  结论  卵巢富细胞纤维瘤是纯间质肿瘤，可有核分裂象增多、伴有少量性索成分及黄素化。部分患者合并胸腹水及CA125升高，易误诊为恶性肿瘤。为避免误诊以影响临床诊断和治疗，认识该病具有重要的意义。      

Prognostic significance of the expression of a ras protein with a molecular weight of 21,000 by human breast cancer

Expression of the cellular ras Mr 21,000 protein (p21) has been measured in tumors from breast cancer patients who at time of presentation had no evidence of metastatic disease. Western blotting analysis revealed that 37 of 54 (69%) tumors contained p21 levels 2- to 10-fold greater than those of control breast tissues. An excessive increase of p21 (5- to 10-fold over the control value) occurred more frequently in tumors of T3 and T4 stages [15 of 25 (60%)] than in tumors at T2 stage [6 of 29 (21%)], suggesting a correlation between advancement of disease and high p21 levels. p21 levels were positively related to the involvement of axillary lymph nodes at the time of primary treatment. As no correlations were detected between p21 levels and a gross pathological parameter, tumor grade, it is possible that p21 levels may reflect the degree of cellular malignancy. This is supported by data on tumor recurrence; 13 of 16 patients (81%) with tumors expressing low p21 levels were disease free for greater than or equal to 4 years after primary treatment, whereas only 5 of 9 patients (56%) with high p21 tumors remained disease free. These results suggested that a quantitative enhancement of p21 oncogene protein is associated with both the progression and prognosis of breast cancer.     

Bcl-2 and MALT1 genes are not involved in the oncogenesis of uterine tumors resembling ovarian sex cord tumors

Uterine tumors resembling ovarian sex cord tumors (UTROSCT) are rare entities. They were described by Clement and Scully in 1976 who classified them into groups I and II. Group I comprises typical endometrial stromal neoplasms with focal areas resembling ovarian sex cord elements and group II are predominantly or completely composed of ovarian sex cord-like elements. We report a case of UTROSCT type II with cytogenetic analysis. The tumor occurred in a 76-year-old woman who presented with vaginal bleeding. The tumor was lobulated, firm, yellow and histologically composed of sex cord-like elements. Tumor cells expressed vimentin, CD10, CD99 and alpha-actin. Cytogenetic analysis in a previously reported case detected translocation t(4;18)(q21.1;q21.3) in the majority of cells. Bcl-2 and MALT1 genes are located at or near the translocation breakpoints, and the aim of this study was to determine whether these genes were involved in chromosomal translocation or tumorigenesis. We did not find IgH translocation or the most common MALT translocations. Bcl-2 was also not involved in this oncogenesis.     

Ovarian Brenner tumors. II. Malignant

In this study, nine malignant Brenner tumors were reviewed and divided into well and poorly differentiated types. To meet the criteria for malignancy, stromal invasion must be observed. A component of typical benign, metaplastic, and/or proliferating Brenner tumor should be identified. The presence of these latter elements is necessary because the malignant component is often too poorly differentiated to be identified as a Brenner tumor, and a metastatic lesion cannot otherwise be ruled out on pathologic grounds. Well-differentiated tumors often occurred in close relationship to proliferating and occasionally to metaplastic areas, and poorly differentiated ones in relationship to low malignant potential areas. The malignant component may consist of transitional cell, squamous, or undifferentiated carcinoma or an admixture of these. A component of adenocarcinoma may be associated with other malignant elements, but pure mucinous or serous adenocarcinomas would be regarded as separate neoplasms. Although the number of cases is small, the well-differentiated tumors appear to have a better prognosis than the poorly differentiated ones.     

Binding of lectins to human mammary tumors: Ultrastructural study

Summary The site of several lectin receptors in human mammary tumors and stroma was studied with the electron microscope. The advantage of the ultrastructural over light microscopic study was that lectin receptors could be localized with precision on the different cell types of the tumor and stroma. Eighteen human mammary carcinomas were incubated with three peroxidase-labeled lectins: peanut agglutinin (PNA),Helix pomatia, andUlex europaeus I (UEA). These lectins reacted in a selective way; some tumors were negative and others showed reaction in some areas of the tumor and/or the stroma. No correlation was found, however, between the presence of these lectin receptors on the tumor cells and either hormone receptors or histological type of the tumors. These results show that the value of the presence of lectin receptors in human mammary tumors as markers for evaluation of mammary lesions is more complex than thought up to now. The most relevant observations on the stroma cells and inflammatory infiltrates were: (A) Some lymphocytes were positive with PNA, probably representing sessile T cells. In two carcinomas, abundant plasma cells were present in the infiltrates, always with PNA receptors. (B) In all mammary tumors where blood vessels were present in the sections, these were always stained with UEA. This supports the use of UEA as a marker for human endothelial cells even in pathologically altered tissues.     

Localized renal cell carcinoma

The last decade has brought dramatic changes in our understanding of localized renal tumors. Due to vast improvements in the abdominal imaging modalities of computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI), approximately two-thirds of patients at our center have their renal tumors discovered incidentally. This tumor stage and size migration has vastly improved survival rates; more than 75% of patients with localized renal tumors achieve cure after surgical resection. In addition, the increased presentation of small, incidental tumors has increased the therapeutic options for urologic surgeons with surgical or tumor ablative techniques who now consider preservation of renal function as a goal equally important to local tumor control. Renal cortical tumors, viewed previously as a single type of cancer (ie, hypernephroma, renal cell carcinoma) with a uniform metastatic potential, are far more complex in nature. Renal cortical tumors are a family of neoplasms with distinct histological subtypes and distinct cytogenetic and molecular defects. Metastatic potential, once thought to be dependent only on tumor size, grade, and stage, varies according to tumor histologic subtype, ranging from the most potentially malignant conventional clear cell carcinoma, to the indolent papillary and chromophobe carcinomas, to the virtually benign renal oncocytoma. Surgical approaches to the localized renal cortical tumors now include the classic radical nephrectomy, kidney-sparing surgery, and innovative techniques that involve laparoscopy. New therapeutic modalities, such as renal cryosurgery and radiofrequency ablation, are under active investigation. Whether these new approaches to localized renal tumors will supplement or replace current surgical techniques will depend on the findings of carefully designed and controlled clinical trials.