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PubMed2004

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas.

Defective DNA mismatch repair has been proposed as a second pathway for colonic carcinogenesis, particularly in tumors arising in the right colon. We investigated whether tumors arising in the appendix are associated with defective DNA mismatch repair using immunohistochemistry for mismatch repair enzymes hMLH-1, hMSH-2, hMSH-6, and hPMS-2. These immunoassays have been shown to be highly sensitive and specific for defective DNA mismatch repair in sporadic and familial adenocarcinomas. Sporadic adenocarcinomas with defective DNA mismatch repair essentially always show loss of hMLH-1, while loss of hMSH-2, hMSH-6, or hPMS-2 is almost always due to germline mutation. In all, 35 cases of appendiceal epithelial neoplasms were evaluated, comprising 18 low-grade appendiceal mucinous neoplasms confined to the appendix; eight low-grade appendiceal mucinous neoplasms with extra-appendiceal spread (five peritoneum and ovaries, two peritoneum, one ovaries only); and nine invasive adenocarcinomas (three with metastatic disease). All immunohistochemical slides were reviewed by two pathologists. One (11%) invasive adenocarcinoma showed absent expression of hMSH-2 and hMSH-6, but preserved hMLH-1 and hPMS-2 expression. This case was a 26-year-old female with a history of synovial sarcoma who presented with acute appendicitis and appendiceal perforation (median age for other invasive carcinomas, 62 years; range 38-76 years). The appendiceal tumor was a moderately differentiated, colonic-type adenocarcinoma without significant extracellular mucin or tumor-infiltrating lymphocytes. The remaining invasive carcinomas and low-grade appendiceal mucinous neoplasms demonstrated preserved expression of all mismatch repair enzymes, including the seven cases in which extra-appendiceal tumor was also evaluated. We conclude that defective DNA mismatch repair does not play a role in the pathogenesis of low-grade appendiceal mucinous neoplasms. Defective DNA mismatch was found in 11% of invasive carcinomas, likely due to a germline mutation. These findings suggest that sporadic appendiceal neoplasia rarely arises through the defective DNA mismatch repair (mutator) pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Sarcomatoid salivary duct carcinoma of the parotid gland.

Salivary duct carcinoma (SDC) is a high-grade neoplasm known to histologically resemble high-grade ductal carcinoma in situ of the breast. We describe 3 cases of sarcomatoid salivary duct carcinoma, a heretofore unreported variant of SDC. Each case was a composite of SDC and sarcomatoid carcinoma and histologically similar to reported cases arising in the breast. The clinicopathologic features, including immunohistochemistry, of 3 cases were investigated. In the 3 men, ages 56, 68, and 70 years, the resected parotid tumors measured 1.5, 3.5, and 1.5 cm, respectively. Only the 3.5-cm tumor extended beyond the parotid gland into soft tissue. This patient died at 3 years with pulmonary metastases. The other patients were free of disease at 6 and 12 months. Histologically, each case was a composite of usual-type SDC and sarcomatoid carcinoma. SDC showed typical cribriform architecture, whereas anaplastic, spindled cells constituted the sarcomatoid areas. Immunohistochemically, epithelial elements stained as follows: cytokeratin (AE1/AE3 & CAM 5.2) positive in 3 of 3 cases, EMA positive in 3 of 3 cases, vimentin negative in 3 of 3 cases, desmin negative in 3 of 3 cases, c-erbB-2 positive in 1 of 2 cases. Sarcomatoid elements stained as follows: AE1/AE3 negative in 3 of 3 cases, CAM 5.2 rare positive cell in 1 of 3 cases, EMA focally positive in 3 of 3 cases, vimentin positive in 3 of 3 cases, desmin negative in 3 of 3 cases, c-erbB-2 negative in 2 of 2 cases. Electron microscopy, performed in one case, showed scattered junctional complexes congruent with epithelial differentiation. Immunohistochemical results, EMA and CAM 5.2 positivity, and ultrastructural findings supported our belief that these unique biphasic tumors represented SDC with sarcomatoid carcinoma. We conclude an element of sarcomatoid carcinoma rarely may arise in association with SDC, and it is erroneous to diagnose such tumors as "carcinosarcoma."

Aged↗

PubMed1984

Issues in the in vivo measurement of glucose metabolism of human central nervous system tumors.

Over 150 cases of central nervous system tumors have been studied with positron emission tomography using fluorine-18-labeled fluorodeoxyglucose (18FDG) as a tracer. From this material 100 consecutive cases of cerebral glioma have been reviewed and analyzed. The results show a strong correlation of tumor grade with glycolytic rate, with visual "hot spots" present in all high-grade neoplasms and in only four low-grade tumors. The quantitative accuracy is limited by three basic factors. First, the measurement of tissue uptake, as compared with the parent technique, autoradiography, is more difficult because detection must be done outside the body. Effects such as scattered radiation and self-attenuation introduce errors unless properly corrected. A more serious problem when measuring small structures, such as a rim-shaped high-grade glioma, is the limited spatial resolution. The most advanced scanner, the Neuro-PET, has a resolution of 6 to 7 mm. Second, corrections are needed for backflow, including free tracer at the time of the scan that will return to the blood and "trapped" tracer that will backflow because of the presence of phosphatase. These corrections are calculated from the blood activity using nominal rate constants for 18FDG. Our study found no significant alteration in rate constants between normal and tumoral tissue. Finally, a lumped constant is needed to correct for kinetic differences between 18FDG and glucose. If there is a change in the mechanism of either membrane transport or the hexokinase reaction, the lumped constant may change. However, measurements of actual glucose utilization in tissue culture lines from six patients support the 18FDG results.

Animals↗

PubMed2001

[Detection of proteins and mRNA of p16, p53 and nm23 in mucoepidermoid carcinoma of salivary glands and their prognostic significance].

OBJECTIVE: To disclose the relationship between the expression of p16, p53 and nm23 and the significant morphologic characteristics in mucoepidermoid carcinoma. METHODS: The proteins and mRNA in paraffin blocks from 41 mucoepidermoid carcinoma patients were studied with immunohistochemical methods and in situ hybridization respectively. RESULTS: The negative expression of p16 was found in 62.5% (15/24) of the low differentiation grade and in 29.4% (5/17) of the high differentiation grade (P = 0.037). The positive p53 expression was detected in 70.8% (17/24) of the low grade neoplasms and in 23.5% (4/17) of the high grade (P = 0.003), while positive nm23 protein was present in 37.5% (9/24) and 64.7% (11/17) respectively (P = 0.086). However, no relationship was found between positive mRNA of p16, p53, nm23 and WHO pathologic grade. CONCLUSIONS: There is a significant correlation between expression of p16 and p53 and WHO pathologic grade of mucoepidermoid carcinoma, which indicates clinical prognostic significance. No correlation is noticed between the pathologic grade and the expression of nm23 protein and mRNAs of p16, p53 and nm23.

Adult↗

PubMed2025

Longitudinal profiling of IDH-mutant astrocytomas reveals acquired RAS-MAPK pathway mutations associated with inferior survival.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant astrocytomas represent the most frequent primary intraparenchymal brain tumor in young adults, which typically arise as low-grade neoplasms that often progress and transform to higher grade despite current therapeutic approaches. However, the genetic alterations underlying high-grade transformation and disease progression of IDH-mutant astrocytomas remain inadequately defined. METHODS: Genomic profiling was performed on 205 IDH-mutant astrocytomas from 172 patients from both initial treatment-naive and recurrent post-treatment tumor specimens. Molecular findings were integrated with clinical outcomes and pathologic features to define the associations of novel genetic alterations in the RAS-MAPK signaling pathway. RESULTS: Likely oncogenic alterations within the RAS-MAPK mitogenic signaling pathway were identified in 13% of IDH-mutant astrocytomas, which involved the KRAS, NRAS, BRAF, NF1, SPRED1, and LZTR1 genes. These included focal amplifications and known activating mutations in oncogenic components (e.g. KRAS, BRAF), as well as deletions and truncating mutations in negative regulatory components (e.g. NF1, SPRED1). These RAS-MAPK pathway alterations were enriched in recurrent tumors and occurred nearly always in high-grade tumors, often co-occurring with CDKN2A homozygous deletion. Patients whose IDH-mutant astrocytomas harbored these oncogenic RAS-MAPK pathway alterations had inferior survival compared to those with RAS-MAPK wild-type tumors. CONCLUSIONS: These findings highlight novel genetic perturbations in the RAS-MAPK pathway as a likely mechanism contributing to the high-grade transformation and treatment resistance of IDH-mutant astrocytomas that may be a potential therapeutic target for affected patients and used for future risk stratification.

IDH1 mutation↗

PubMed1996

[Reproducibility of nuclear grade in breast neoplasm. A multicenter experience].

Nuclear grade is considered a valuable prognostic factor in mammary carcinomas. Since the histological diagnosis of most of these tumors is made by "non expert" pathologists, it was considered interesting to find out the reproducibility of general pathologists to define the nuclear grade. In order to do this, a series of 15 mammary carcinomas, 10 of them randomly selected and 5 because they were considered difficult to classify for nuclear grade, were examined separately by 10 general pathologists. In a first round of observation, each one of them graded the cases according to their own criteria as used routinely, and for a second round they followed a written guide. An analysis of variance was applied to the data and no significant differences were found between observers, neither in the randomly selected cases nor in the total series. The written guide, surprisingly, instead of lowering the differences, increased them. Analysis of the individual performance of observers showed two of them having a great variation between both rounds of observation, and this was considered to influence the results of the whole group. Interobserver performance to discriminate high grade tumors (G3) from the rest, showed a good correlation in all the participants. These results allow us to conclude that in this series, examined by general pathologists, an acceptable reproducibility was observed, specially when high risk tumors were being identified.

Analysis of Variance↗

PubMed2001

Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasms.

We morphometrically evaluated 5-micron H&E-stained sections from 28 surgically resected high-grade pulmonary neuroendocrine neoplasms, including 16 small cell lung carcinomas (SCLCs) and 12 large cell neuroendocrine carcinomas (LCNECs). For each case, 200 tumor nuclei and 20 to 100 normal lymphocytes were measured. The frequency distributions of tumor cell/lymphocyte (TC/L) size ratios were plotted in bins ranging from 1 to 6, classified into 6 histogram types with TC/L size ratio peaks ranging from 2 to 6 (A-E) and a histogram with a wide distribution (F). SCLCs fit histograms A through E; LCNECs, A through F. Morphometry demonstrated considerable nuclear size overlap in high-grade neoplasms. Approximately one third of SCLCs exhibited considerable numbers of neoplastic cells that were larger than 3 normal lymphocytes, while 4 of 12 LCNECs had a predominant number of small cells. Ten tumors exhibited a B histogram with a "borderline" peak TC/L of 3. The rule that a TC/L size ratio larger than 3 helps distinguish "large" from "small" neoplastic cells was confirmed in only 9 of 28 cases. The use of more generic terminology such as "high-grade neuroendocrine carcinoma" or "grade III neuroendocrine carcinoma" for SCLC and LCNEC is discussed.

Carcinoma, Neuroendocrine↗

PubMed2003

Potential role of bcl-2 and ki-67 expression and apoptosis in colorectal carcinoma: a clinicopathologic study.

Colorectal cancer is associated with deregulation of apoptotic and proliferative processes. The purpose of this study was to investigate the presence of apoptosis and proliferation in colorectal cancer and evaluate their possible correlation with classic prognostic markers and patients' survival. Tumors from 117 patients, followed for 44-142 months, were studied immunohistochemically using the anti-bcl-2 and anti-Ki-67 antibodies. Apoptotic body index (ABI) was assessed by a standard TUNEL method. The bcl-2 protein was detected in 65% of adenocarcinomas with increased expression in low-grade and early-stage tumors. No association was noted between bcl-2 expression and proliferative activity, ABI, or patients' survival. A positive correlation was observed between ABI and proliferation (P < 0.05). Apoptosis was more frequently observed in advanced tumor stage or high-grade neoplasms. Cox analysis revealed that only tumor stage and grade constituted independent prognostic factors. The study suggests that there is a possible deregulation of the mechanisms that control bcl-2 expression in high-grade and advanced-stage colorectal carcinomas. Regulation of apoptosis is a complex phenomenon and other factors, including tumor heterogeneity, may be involved.

Adenocarcinoma↗

PubMed1993

Premalignant nonepithelial lesions: a biological classification.

Premalignant lesions occur early in neoplastic development, are often small and multiple, lack one or more of the properties of cancers, often regress, and are often easily treatable. Such lesions may be derived from epithelial or nonepithelial cell populations. Many epithelial premalignant lesions can be identified by their confinement by a basement membrane. Mesenchymal, hematologic, and lymphoid premalignant lesions are difficult to recognize as most of these lesions have no defining morphologic features or anatomic boundary that identifies their premalignant nature. We have devised a classification for nonepithelial premalignant lesions, based on biologic behavior rather than morphology, that includes neoplastic lesions that have some but not all of the properties generally attributed to developed cancers. The five categories of nonepithelial premalignant lesions are: (a) lesions delimited by a basement membrane (e.g., melanoma in situ); (b) nonepithelial neoplasms having a low rate of metastasis (e.g., giant cell tumor of bone); (c) early forms of nonepithelial malignancy (e.g., Kaposi's sarcoma, patch stage); (d) indolent neoplasms that regularly progress to malignancies (e.g., chronic lymphocytic leukemia); and (e) certain low-grade neoplasms derived from germ cells (e.g., Grade 1 immature teratoma). Formal classification of the nonepithelial premalignant lesions would allow the pathologist to diagnose these biologically distinct entities as something other than simply benign or malignant, and would direct tumor biologists to study the key molecular properties that control the premalignant phenotype.

Basement Membrane↗

PubMed2005

Sclerosing epithelioid fibrosarcoma: a case report.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma. It is a mesenchymal neoplasm composed of round to oval cells dispersed in a nestlike or cordlike distribution on a highly collagenous tissue background and is now recognized as a distinct clinical entity. In this report we discuss the presentation, diagnosis, and treatment of SEF. We focus on the unique histologic and immunohistochemical properties of this lesion. It is essential for both the surgeon and the pathologist to be aware of SEF and include it in the differential diagnosis for atypical head and neck neoplasms. Sclerosing epithelioid fibrosarcoma is a rare neoplasm that is now listed among the low-grade neoplasms that may occur in the head and neck. However, its behavior tends to be typical of more aggressive lesions. An awareness of this characteristic of SEF is essential for clinicians and pathologists alike.

Adult↗

PubMed2000

Detection of pulmonary metastasis of low-grade endometrial stromal sarcoma 25 years after hysterectomy.

Endometrial stromal sarcoma (ESS) is a rare uterine sarcoma. Low-grade ESS occasionally recurs or metastasizes after long disease-free periods, a fact that may complicate the diagnosis. Here we report a case of multiple lung metastases in a 68-year-old woman who had been disease-free for 25 years after hysterectomy for a uterine tumor. Biopsy revealed that the tumor was composed of oval cells with slight nuclear atypism but without mitotic figures, suggesting a low-grade neoplasm. Immunostaining for intermediate filaments revealed strong positivity for vimentin and weak positivity for alpha-smooth muscle actin. In addition, immunostaining for estrogen and progesterone receptors, performed under suspicion of low-grade ESS, was positive. The uterine tumor resected many years before had shown a similar morphology. Thus, it was demonstrated that the lung neoplasm was a metastatic low-grade ESS that had appeared after many disease-free years. A review of the literature revealed that this case had the longest recorded interval between the occurrence of the initial ESS and the development of distant metastases. When low-grade sarcoma appears in the lungs of female patients, it is important to consider the possibility of low-grade ESS. Detailed information on the past clinical history, together with immunostaining for estrogen and progesterone receptors, are important diagnostic keys.

Disease-Free Survival↗

PubMed1999

Well-differentiated intraosseous osteosarcoma of the jaws: experience of two cases from the Instituto Nacional de Cancerología, México.

Osteosarcomas of the jaws represent less than 10% of all osteosarcomas, and most of them are high-grade neoplasms. Prognostic factors in overall survival include tumor size, location and histologic grade. Examples of well-differentiated (low-grade) intraosseous osteosarcomas of the jaws (WDIOJ) have been rarely reported. This article presents two cases of this unusual lesion, one of which was located in the maxilla of a 17-year-old man and the other developed in the mandible of a 37-year-old woman. CT scan was necessary to detect the small foci of penetration into the thinned cortical bone and the reactive periosteal bone formation, which are important findings to establish the correct diagnosis of WDIOJ and help to exclude other benign intraosseous lesions that may be very similar histologically, such as fibrous dysplasia, ossifying and desmoplastic fibromas. In spite of tumor size (mean 5.2 cm), their well-demarcated borders allowed complete removal of both tumors. There is no evidence of tumoral activity in any of our patients after follow-up periods of 15 months and 5 years. Wide excision seems to be the treatment of choice for this subgroup of osteosarcomas.

Adolescent↗

PubMed1994

Tumor necrosis factor-alpha mRNA and protein in endometrial tumors: analysis by in situ hybridization and immunocytochemistry.

Abnormal expression of polypeptide growth factors and their receptors is closely associated with tumorigenic transformation. In this study tumor necrosis factor-alpha (TNF-alpha) mRNA and protein were analyzed in polyps and proliferative lesions of endometrium as well as in low and high grade endometrial tumors by using in situ hybridization and immunocytochemistry. All samples contained products of the TNF-alpha gene. Histochemical scores (HS), which reflect the proportion of cells positive for TNF-alpha message or protein and the intensities of the signals, were higher for epithelial than for stromal cells. Benign lesions (endometrial polyps) contained little TNF-alpha mRNA or protein, whereas specific message was abundant in proliferative lesions (hyperplasia, adenofibroma). Although neoplastic cells in both low and high grade endometrial tumors contained TNF-alpha mRNA, two major differences were observed: HS for TNF-alpha mRNA were significantly less in low grade than in high grade neoplasms, and TNF-alpha message was restricted to the nucleus in low grade adenocarcinoma cells but was abundant in the cytoplasm of high grade tumor cells. In contrast to cells in benign and proliferative lesions, TNF-alpha protein scores in endometrial tumor cells were inversely rather than positively correlated with TNF-alpha mRNA scores. Collectively, the findings in this study are consistent with the postulate that TNF-alpha is useful to endometrial tumor cells and suggest that production may increase as cells diverge from normal.

Adenocarcinoma↗

PubMed2005

CD10 immunohistochemical staining in urothelial neoplasms.

CD10, or common acute lymphoblastic leukemia antigen, is a cell surface neutral endopeptidase that inactivates various bioactive peptides. It is expressed by hematopoietic cells and their neoplasms and in a variety of nonhematopoietic tissues and neoplasms. CD10 has been suggested as a useful marker for urothelial carcinoma, but the few studies of CD10 in urothelial tissues have shown varying results; a comparative study of the CD10 immunoprofile in a range of urothelial tumors has not been performed. We report the CD10 immunoprofile of 70 cases representing urothelial lesions as defined by the World Health Organization Classification (2004) of urothelial neoplasia. We demonstrated moderate to strong CD10 immunohistochemical staining in 67% (40/60) of urothelial neoplasms, with a predominantly cytoplasmic staining pattern. We found a statistically significant difference in staining intensity (scale, 0-3) between high-grade neoplasms (mean, 2.5), dysplasia (mean, 1.7), and low-grade lesions (mean, 1.3), with the high-grade group showing a propensity for a more diffuse staining distribution than the low-grade group. Larger studies incorporating molecular genetic techniques should help better define the role of CD10 in urothelial tumorigenesis.

Humans↗

PubMed1991

Well-differentiated extraskeletal osteosarcoma. A soft-tissue homologue of parosteal osteosarcoma.

We describe a unique case of a low-grade extraskeletal osteosarcoma revealing both histologic and radiologic features reminiscent of parosteal osteosarcoma. The tumor, which had been present for 10 years, occurred in the left axilla of a 74-year-old black woman. To date, all the published cases of extraskeletal osteosarcoma have been high-grade neoplasms; to our knowledge, this is the first reported case of a low-grade extraskeletal osteosarcoma.

Aged↗

PubMedDate not supplied

[A case of recurrent cough in bronchial carcinoid].

The carcinoid tumors of the bronchial are extremely uncommon, with an incidence of 5% of all pulmonary neoplasms. The carcinoid is the more frequent tumor of the lung in paediatric age. The symptoms most often reported were cough, recurring infection, chest pain, hemoptysis, fever, dyspnea, mild dyspnea attacks after physical effort or nervousness. The carcinoid syndrome is uncommon. Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid, intermediate-grade atypical carcinoid, and high-grade categories of large cell neuroendocrine carcinoma and small cell carcinoma. Low grade neoplasms may metastasize to adjacent nodes. Atypical carcinoids are considered low grade malignancies. Most malignant end of neuroendocrine neoplasm group is small cell carcinoma. Typical carcinoids carry an excellent prognosis and should be offered conservative lung resection, whilst atypical carcinoids which behave aggressively should be treated by radical lung resection. The authors report a case of the young patients with bronchial typical carcinoid tumor who had suffered from cough and mild dyspnea attacks after physical effort or nervousness in the last year.

Bronchial Neoplasms↗

PubMed1997

The myoepithelial defense: a host defense against cancer.

The behavior of human tumors depends not only on the nature of the tumor cells themselves but also on the modifying effects of various normal host cells such as fibroblasts and endothelial cells. One cell type, however--the myoepithelial cell--has not been studied scientifically. Myoepithelial cells normally surround ducts and acini of glandular organs such as the breast and salivary glands and contribute to the synthesis of a surrounding basement membrane. This relationship suggests that myoepithelial cells may exert paracrine effects on glandular epithelium and also regulate the progression of ductal carcinoma in situ (DCIS) to invasive carcinoma. Myoepithelial tumors, in turn, tend to be benign or low-grade neoplasms that exhibit the rare property of accumulating rather than degrading extracellular matrix material. To better understand the nature of myoepithelial tumors, as well as the possible role of normal myoepithelial host cells in cancer, we have established immortal cell lines and a number of transplantable xenografts from various human myoepithelial tumors of the salivary gland and breast. The cell lines exhibit a normal myoepithelial phenotype and the xenografts continue to accumulate an abundant extracellular matrix. Further ultrastructural, immunocytochemical, molecular, and biochemical studies reveal that myoepithelial cells secrete relatively low levels of matrix-degrading proteinases but relatively high levels of maspin and various other anti-invasive proteinase inhibitors, that some of these inhibitors accumulate within the myoepithelial matrix, and that myoepithelial cells can induce epithelial morphogenesis (spheroid formation) and inhibit tumor-cell invasion in vitro. Myoepithelial cells, which surround normal breast ducts and DCIS, have also been found to selectively express maspin and certain proteinase inhibitors in situ. These inherent myoepithelial properties are likely to contribute to the low-grade nature of myoepithelial neoplasms and advance our hypothesis that host myoepithelial cells regulate the progression of in situ to invasive carcinoma by providing an important host defense against cancer invasion.

Animals↗

PubMed1983

Morphology and biology of cerebellar neuroblastomas.

A nodular neuroblastoma was partially removed from the cerebellar vermis of a 15-month-old boy. Postoperative irradiation and chemotherapy were performed. More than 5 years later, re-operation revealed a mature ganglioglioma. Problems relating to the maturation of ganglionic tumors are discussed. The present case emphasizes that it is not justified to regard all neuroblastomas of the central nervous system as highly malignant neoplasms (grade IV).

Adolescent↗