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Ultrastructure of canine, feline, and bovine mast cell neoplasms.

Biopsy specimens were collected from skin or spleen from 8 dogs, 7 cats, and 1 cow with mast cell neoplasms. Following histopathologic grading, the neoplasms were examined by transmission electron microscopy with the intention of reviewing their fine structure and recording new findings. For 2 feline specimens, short-term cell cultures were established, and adherent cells were fixed in situ and examined with the electron microscope. In addition to the usual array of mast cell organelles, including Golgi apparatus, secretory granules, mitochondria, vesicles, tubules, microfilaments, and ribosomes, important findings included coarse interdigitation of cytoplasmic projections between adjacent mast cells; intracytoplasmic parallel stacks of 10 nm diameter filaments as well as parallel arrays of coarse, 120 to 150 nm diameter tubules; the appearance of coated vesicles and caveolae on cell surfaces; the appearance of endocytosed erythrocytes; and the formation of giant secretory granules.

Animals↗

Methylation of the E-cadherin gene in bladder neoplasia and in normal urothelial epithelium from elderly individuals.

Decreased expression of the epithelial cell adhesion protein E-Cadherin occurs in several forms of human epithelial-derived cancers, including bladder cancers. We investigated the possibility that aberrant methylation of the CpG island flanking the 5' transcriptional start site of the e-cadherin gene is responsible for the decreased expression of this gene in bladder cancer, similar to the relationship previously seen between e-cadherin methylation and gene expression in other types of human cancers. Using methylation-specific polymerase chain reaction, we found methylation of this CpG island in 20 of 47 cases (43%) of bladder neoplasms ranging from low-grade papillary neoplasms to advanced, invasive cancers. When methylation status was compared to immunochemical staining for E-Cadherin, we found significantly diminished levels of E-Cadherin expression in 14 of 15 cases (93%) with methylation of the gene. We also found decreased expression of E-Cadherin, although to a somewhat lesser extent, in a high percentage (77%) of the cases without methylation of the gene. Although these data suggest a relationship between e-cadherin CpG island methylation and decreased gene expression, it evident that other mechanisms also contribute to decreased expression of this gene in bladder neoplasia. Remarkably, we also found low levels of e-cadherin methylation in urothelial cells from three of nine (33%) histologically normal bladders, with all three of the normal bladder samples with methylated e-cadherin being from individuals older than 70 years of age. Thus, methylation of the e-cadherin CpG island may occur normally in this tissue with aging as well as in low-grade papillary neoplasms, and is not specific to cancer in the bladder. This finding of methylation in normal urothelial cells from elderly individuals is provocative with respect to a possible link between aging and increased risk for bladder cancer, but it suggests limitations on the usefulness of using methylation of e-cadherin as a molecular marker for detection of bladder cancer.

Adult↗

Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues.

Expression of monocarboxylate transporter MCT1 was studied in archival tissues from human CNS using antibodies to the carboxyl-terminal end of MCT1. Sections of neocortex, hippocampus and cerebellum of brains from 10 adult autopsy patients who died from other than CNS disease, and from archival surgical biopsy specimens of 83 primary CNS and eight non-CNS tumors were studied. MCT1 immunoreactivity was present in microvessels and, ependymocytes of normal CNS tissues similar to that reported for MCT1 expression in rat brains. MCT1 immunoreactivity was strongest in ependymomas, hemangioblastomas and high grade glial neoplasms, and weakest in low grade gliomas. Increased MCT1 expression in high grade glial neoplasms may provide a potential therapeutic target for treatment of some CNS neoplasms.

Antibodies↗

Twice-daily, split-course abdominopelvic radiation therapy after chemotherapy and positive second-look laparotomy for epithelial ovarian carcinoma.

Between July 1983 and December 1988, 34 patients with ovarian carcinoma received whole abdominal irradiation in an attempt to eliminate residual disease following second-look laparotomy. Three additional patients who had initial complete responses to chemotherapy were treated for a recurrence of their disease. All patients had been treated with chemotherapy that included cisplatin and cyclophosphamide. Three patients had also received doxorubicin with some or all chemotherapy cycles. Thirty Gray of abdominopelvic radiation therapy (APRT) was delivered using a twice-daily, split-course schedule. Eleven patients also had a boost of 9-20 Gy to sites of residual disease. Treatment was well tolerated. Only one patient did not complete therapy and two patients had 1-week prolongations of treatment because of hematologic toxicity. Thirty-two percent of patients had grade 2 neoplasms and 61% had grade 3 disease. Three patients with grade 1 tumors continue to have no evidence of disease 20-50 months after irradiation. Patients with grade 2 and 3 neoplasms who had microscopic residual disease prior to APRT had relapse-free survival rates at 3-years of 10% and 14%, respectively. Twelve patients with gross residual disease had rapid recurrences (median time to relapse, 4.9 months) and all have died of their disease. Although 14 patients (38%) have experienced small bowel obstructions, all of these had known recurrent abdominal disease at the time. Twenty patients (54%) had undergone more than two abdominal surgeries prior to APRT, and several were noted to have extensive adhesions at second-look laparotomy. None of the five patients currently believed to be free of disease has experienced a small bowel obstruction. Radiation is only one of several factors that contributed to bowel obstructions. Although APRT may be able to eliminate residual disease in a small proportion of patients with microscopic residual disease after chemotherapy, the aggressive biology of tumors that respond incompletely to chemotherapy and the compromises in radiation dose and schedule that must be made in these heavily treated patients probably contribute to the disappointing results of this treatment.

Antineoplastic Combined Chemotherapy Protocols↗

Cyclin D1 immunohistochemical staining is useful in distinguishing mantle cell lymphoma from other low-grade B-cell neoplasms in bone marrow.

The distinction between mantle cell lymphoma (MCL) and other low-grade B-cell neoplasms is important because MCL has a more aggressive clinical course. In bone marrow biopsy specimens, this distinction can be especially difficult. We examined 70 bone marrow biopsy specimens involved by various B-cell lymphoid neoplasms to assess the utility of cyclin D1 immunostaining in distinguishing MCL from other B-cell lymphoproliferative disorders. We used a cocktail of two monoclonal anti-cyclin D1 antibodies and a heat- and sonication-induced epitope retrieval procedure. The neoplasms assessed included MCL (32 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (18 cases), follicular lymphoma (11 cases), hairy cell leukemia (5 cases), splenic marginal zone lymphoma (2 cases), and small lymphocytic lymphoma with plasmacytoid differentiation (2 cases). The diagnosis of MCL in bone marrow was confirmed by review of the original diagnostic biopsy specimens along with additional data, such as immunophenotypic or molecular studies. Most MCL (23/32; 72%) cases expressed cyclin D1 protein. In contrast, one case of small lymphocytic lymphoma/chronic lymphocytic leukemia (1/18; 6%) and one case of hairy cell leukemia (1/5; 20%) expressed cyclin D1 protein. These findings demonstrate that immunostaining for cyclin D1 protein expression is useful in distinguishing MCL from other B-cell lymphoid neoplasms in the bone marrow.

Antibodies, Monoclonal↗

Fine needle aspiration cytology of a low grade myxoid renal epithelial neoplasm: a case report.

BACKGROUND: Recently, several case reports have described a rare but distinct subtype of renal tumor, referred to as a "low grade renal epithelial neoplasm," that appears to have a better prognosis than conventional renal cell carcinoma does. This report describes the cytologic features of this tumor as determined by fine needle aspiration (FNA) biopsy. CASE: A 53-year-old woman with a history of lymphoma had a renal mass incidentally discovered on an abdominal computed tomographic scan performed for lymphoma restaging. Results of an FNA biopsy showed relatively uniform, medium-sized tumor cells with moderate amounts of finely vacuolated or wispy cytoplasm and indistinct cell borders. The nuclei were primarily round with coarse chromatin and had prominent nucleoli. In the cell block preparation, the tumor cells showed a tubular architecture and an abundant myxoid matrix. The patient underwent a partial nephrectomy. The tumor was classified as a low grade myxoid renal epithelial tumor. CONCLUSION: This unusual kidney tumor appears to have distinctive cytomorphologic features, including a uniform population of epithelial cells with round nuclei, an abundant myxoid matrix and tubular architecture.

Biopsy, Fine-Needle↗

Graded compression sonography of abdominal neoplasms mimicking acute appendicitis.

Over a 3-year period nine patients (mean age of 43 years) with acute abdominal pain and unsuspected abdominal neoplasms were referred for graded compression sonography to rule out appendicitis. Six of the nine patients had right lower quadrant neoplasms involving the cecum, terminal ileum, iliacus muscle, or iliac lymph nodes. However, in three patients neoplasm was noted outside the right iliac fossa involving the liver, right kidney, and upper abdominal mesentery. This study underscores the fact that in patients without sonographic evidence of acute appendicitis, a survey of the upper abdomen and right flank should routinely be performed in addition to scanning the right iliac fossa and pelvis. In patients more than 50 years of age neoplasm must also be kept in mind in the differential diagnosis of appendicitis.

Abdominal Neoplasms↗

Grade progression and high-grade transformation in neuroendocrine neoplasms.

Epithelial neuroendocrine neoplasms (NENs) comprise a biologically diverse group of malignancies that span a wide spectrum of differentiation, proliferative activity, and clinical behavior. Contemporary classifications distinguish well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinomas (NECs). However, growing longitudinal data indicate that a subset of NETs may undergo temporal evolution characterized by rising Ki-67, increasing morphologic atypia, and acquisition of genomic alterations classically associated with NEC, particularly TP53 and, less commonly, RB1 inactivation. These phenomena, referred to as grade progression and high-grade transformation, can result in tumors with NEC-like behavior despite retention of a NET molecular backbone, creating diagnostic and therapeutic ambiguity. In this review, we synthesize recent evidence on the molecular, morphologic, and clinical features of gastroenteropancreatic NET grade progression and transformation, highlight the role of clonal evolution and treatment-associated selection pressure, and discuss implications for imaging, biopsy strategy, molecular profiling, and therapy selection.

Humans↗

Malignant potential of intrahepatic biliary papillomatosis: a case report and review of the literature.

BACKGROUND: Biliary papillomatosis (BP) is a rare disease entity with a strong malignant potential. It is characterized by multiple papillary adenomas involving both the intrahepatic and extrahepatic biliary tree. BP was considered in the past to be a disease with low malignant potential. However, a current review of the English literature revealed a high rate of malignant occurrence of approximately 41% and histological analysis along with the expression pattern of mucin core proteins (MUC) and mucin carbohydrate antigens suggests that BP is a borderline or low grade malignant neoplasm with a high malignant potential. CASE PRESENTATION: A 68 year-old male patient was referred to our hospital due to the presence of sudden right upper quadrant abdominal pain, nausea and dark urine. Imaging workup demonstrated dilatation of the left hepatic duct without the presence of a space-occupying lesion. A left hepatectomy and cholecystectomy were carried out and histological analysis revealed a moderately to poorly differentiated carcinoma of the left hepatic duct in the background of biliary papillomatosis. Postoperative course was uneventful. Unfortunately, two years after initial diagnosis the patient rapidly deteriorated and died from multiple pulmonary secondary deposits. CONCLUSION: BP should not be considered to be a benign disease. The clinical behavior, the high recurrence rate and the even higher malignant transformation occurrence, as well as the presence of carcinogenetic indicators (K-ras mutation, overexpression of p53, MUC and Tn antigens) strongly support that BP is a low-grade neoplasm with high malignant potential.

Journal Article↗

The utility of MIB-1/Ki-67 immunostaining in the evaluation of central nervous system neoplasms.

The diagnosis and assignment of grade in neoplasms of the central nervous system (CNS), for the most part, are morphologically based and predicated on the interpretation of descriptions of what the phenotypic findings are for a particular tumor type. Not surprisingly, the application of various grading systems in CNS neoplasia has been limited somewhat by interobserver variability. Since assignment of grade and tumor type is the basis upon which therapeutic intervention is grounded, investigators have been searching for ancillary means by which morphologically based systems can be improved. Utilization of cell proliferation markers in the evaluation of tumors can be potentially useful in this endeavor. This review focuses on issues surrounding the utilization of MIB-1 or Ki-67 antibody in the evaluation of CNS neoplasms.

Antibodies, Antinuclear↗

The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms.

Follicular lymphoma (FL) and B-cell chronic lymphocytic leukemia (B-CLL) are paradigmatic examples of lymphoid malignancies in which the relevant biological mechanisms are alterations in the control of apoptosis rather than an exaggerated proliferation. This explains why low-grade B-cell neoplasms still fail to be cured with current approaches. It is becoming increasingly clear that the defective apoptosis of FL and B-CLL has to be ascribed not only to intrinsic defects of the neoplastic cells, but also to extrinsic factors that influence their behavior. Malignant B cells retain the capacity to respond to microenvironmental signals, but have devised a monothematic responsiveness. They have a specific sensitivity to anti-apoptotic signals that favor their survival, whereas they seem to have become insensitive to pro-apoptotic signals. Bystander, nontumoral cells play a fundamental (though not sufficient) role both in the onset and in the progression of these diseases. The survival of leukemic cells appears to be dependent on direct cell-cell contacts. The localization of malignant B cells in bone marrow or neoplastic follicles is not a passive adhesion phenomenon but a crucial step for their survival. Bidirectional malignant lymphocyte-nontumoral cell interactions may lead to the amplification of a microenvironment able to inhibit the apoptosis of neoplastic B cells. The pressure of antigenic selection and the role of the tumor necrosis factor receptor family through the functional survival signal provided by CD40 together with the crippled death signal exerted by CD95 are new prominent characters on the stage.

Antigens, CD↗

Monocytoid B-cell lymphoma: its evolution and relationship to other low-grade B-cell neoplasms.

Monocytoid B-cell lymphoma (MBCL) is a newly recognized B-cell neoplasm of uncertain histogenesis. The cytologic features of the neoplastic monocytoid B lymphocytes are virtually identical to those of hairy cell leukemia (HCL). As with HCL, progression of MBCL to a higher histologic grade is very unusual. However, whereas circulating leukemic cells are a characteristic feature of HCL, peripheral blood involvement has not been reported in MBCL. We recently studied a patient with MBCL of the spleen and axillary lymph nodes who developed peripheral blood involvement by MBCL cells. Unlike the cells of HCL, the circulating MBCL cells exhibited strong acid phosphatase activity that was tartrate sensitive. The leukemic cells had the antigenic phenotype IgM lambda, CD20+, CD11c+, CD5-, CD25(TAC)-, and PCA-1-. Immunogenetic studies of both lymph node and peripheral blood cells revealed identical immunoglobulin heavy-chain gene rearrangements. When compared with a series of HCL, the immunophenotype was similar except for the absence of PCA-1 and TAC. Progression of the MBCL to a large cell lymphoma, also expressing IgM lambda, was documented in an abdominal lymph node of this patient. Therefore, although rare, peripheral blood involvement by lymphoma cells may occur during the course of MBCL and should be distinguished from HCL with cytochemical and immunophenotypic studies. In addition, comparison of the clinical, pathologic, and immunologic features of MBCL with those of other low-grade B-cell neoplasms suggests that a close lineage relationship exists between MBCL and HCL.

Adult↗

Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases.

Fifty-eight immature ovarian teratomas were studied. Neoplams with other germ cell elements (endodermal sinus tumor, choriocarcinoma, and dysgerminoma) were excluded so that the clinical and pathologic features of "pure" immature teratomas could be defined and correlated with the prognosis. The primary tumors and their metastatic growths were graded from 0 to 3. Forty were stage I; nine, stage II; and nine, stage III. The size and stage of teratomas were related to survival, but it was the grade of the primary tumor that best determined the likelihood of extraovarian spread, and it was the grade of the metastases that related best to the subsequent course. Actuarial survival was 63% at 5 years and also at 10 years. Regardless of the grade of the primary tumor, only one of six with grade 0 metastases progressed, and that neoplasms may not have been adequately sampled. Two of five neoplasms having grade 1 metastases did not progress, and two of six patients with grade 2 metastatic growths were living after relatively long intervals. All seven patients with grade 3 metastases died with tumor, none surviving more than 2.1 years. Survival of patients with grade 1, 2, and 3 neoplasms was 81, 60, and 30% respectively. The importance of adequate sampling of primary tumor and metastases for estimating prognosis and determining therapy is stressed.

Adnexa Uteri↗

Aggressive bladder carcinoma in a child.

The brief report describes an unusual case of high grade bladder neoplasm with divergent differentiation in a 31 month-old child. The presentation included hematuria with tissue fragments and the tumor was confined to the bladder. The tumor behaved aggressively despite radical cystectomy, chemotherapy with agents known to be effective against epithelial and mesenchymal tumors and radiation therapy. Although rare, most malignant bladder neoplasms in children are low grade and present in early stages. Sarcomatoid differentiation in the setting of high-grade urothelial carcinoma portends a poor prognosis.

Black People↗

Primary epithelial neoplasms and other epithelial lesions of the appendix (excluding carcinoid tumors).

Epithelial tumors of the appendix range from low-grade mucosal-based tumors which, when confined to the appendix, have an excellent prognosis but, once outside the appendix, have a fair prognosis and often a prolonged disease course, to high grade invasive carcinomas that are rapidly fatal. Low grade mucinous neoplasms may rupture and spread to the peritoneum as pseudomyxoma peritonei, and the nomenclature of these tumors has been the subject of considerable disagreement among pathologists; the designation "low grade appendiceal mucinous neoplasm" has recently been proposed for reasons discussed herein. Demonstrating rupture of these neoplasms may require particularly diligent gross and microscopic evaluation as the rupture site often heals over leaving only subtle evidence of its presence. Invasive adenocarcinomas are often mucinous and may also spread to the peritoneum. Against this backdrop, the clinical and pathologic features of low grade appendiceal mucinous neoplasms and mucinous adenocarcinomas, as well as other types such as typical colorectal type and signet-ring cell type, are reviewed. In addition, emerging entities, serrated polyps and serrated adenomas, whose significance is only beginning to be understood, are considered. Retention cysts, hyperplastic polyps, and diffuse mucosal hyperplasia, although not necessarily neoplastic, are reviewed here as they may enter into the differential diagnosis of appendiceal mucinous neoplasms.

Appendiceal Neoplasms↗

Histopathologic grading of salivary gland neoplasms: II. Acinic cell carcinomas.

Acinic cell carcinomas display varied cytoarchitectural patterns of growth that should allow for formulation of histopathologic grading. Grading of these carcinomas may serve to identify subsets whose biologic behavior is more aggressive than the usually accepted low-grade behavior of acinic cell carcinomas as a group. To that end, a three-level histopathologic grading scheme is presented.

Carcinoma↗

Expression of CD44 in human neoplastic and normal hyaline cartilage.

Although low-grade cartilage neoplasms typically consist of hyaline-like cartilage, most of them also contain some fibrocartilaginous regions. CD44, a cell surface receptor for hyaluronan, has been identified in cartilage. A family of alternatively spliced mRNA containing the variant 6 (v6) exon sequence of CD44 has been linked to several types of neoplasms. We hypothesized that expressions of v6-containing CD44 species are associated with fibrocartilaginous regions of low-grade cartilage neoplasms. To test this hypothesis we performed reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical analysis on eight samples: four from normal articular cartilage, one from a synovial chondromatosis, and three chondrosarcomas which were graded as I and I/II. The standard CD44s and a unique v6-containing CD44 species (CD44v6-10) were identified in all tissue samples by RT-PCR analysis. Immunohistochemically, using an antibody that cross-reacted with all CD44 species, CD44 was localized to the cell surface, lacuna wall and intracellular compartment of the chondrocytes in the middle and deep zone of normal cartilage, as well as with cells throughout the neoplastic masses. Utilizing an antibody specific for v6-containing CD44 species, the variant species was identified throughout cells of the middle and deep zone of normal cartilage, and localized selectively to intracellular positions. In neoplastic masses, v6-containing CD44 species were found associated only with cells in the hyaline-like cartilage, but not in the fibrocartilaginous regions. Thus a differential expression of the v6-containing CD44 species in the neoplastic masses containing both hyaline-like cartilage and fibrocartilaginous regions was observed when compared to its homogenous expression in normal hyaline cartilage. An involvement between the lack of the variant CD44 (v6-containing) and altered tissue phenotype (e.g., fibrocartilaginous) is suggested.

Bone Neoplasms↗

Pattern of gene alterations in intraductal breast neoplasms associated with histological type and grade.

To reveal any association between the histological type and grade of intraductal breast neoplasms and the manner of accumulation of gene alterations, eight types of gene alterations, i.e., loss of heterozygosity (LOH) on chromosomal arms 16p, 16q, 17p, 17q, and 18q, amplification of the c-erbB-2 and hst-1/int-2 genes, and mutation of the p53 gene, were examined by Southern blot analysis or single-strand conformation polymorphism analysis in a total of 60 cases of intraductal breast cancer and 18 nonmalignant proliferative lesions. Among the histological types and three histological grade groups of intraductal carcinomas, the gene alterations which occurred most frequently were LOH on 16q alone in non-comedo type and Grade 1, alterations of c-erbB-2, 17p, and 16q in comedo type and Grade 2, and alterations of 17q and p53 as well as those of 16q, 17p, and c-erbB-2 in Grade 3. LOH on 16q and 18q was frequent in intraductal carcinoma of the intracystic papillary type, whereas LOH on 18q alone was detected in 27% of papillomas. Among intraductal carcinomas, the mean number of gene alterations was largest in comedo type and Grade 3, whereas it was smallest in non-comedo type and Grade 1. It was possible that LOH on 18q and 16q was involved frequently in papillary tumori-genesis and acquisition of malignant phenotype, respectively, whereas most of the other gene alterations were involved in acquisition of aggressive biological properties by intraductal carcinoma cells. It was also possible that the phenotype of breast neoplasms was determined by the combination of gene alterations at a relatively early developmental stage.

Breast Neoplasms↗