Biomedical subjects
Publications and source records attributed to D M Parham.
The finding of granulomata in nasal polyps is rare. In this report we describe a case with necrotizing granulomata occurring after surgery. The differential diagnosis of such a finding is discussed.
A prospective autopsy study of deaths of women who had been diagnosed previously as having cancer of the breast was performed between October 1986 and December 1990. During the study period 28 deaths occurred and nine of these (32%) were attributable directly to breast cancer; a figure similar to that found in our earlier retrospective study. In this study the autopsy findings in both the breast cancer and non-breast cancer deaths were recorded and five cases underwent post-mortem radiological skeletal survey to detect metastases. The findings confirm the role of the post mortem in modern medicine as a method of auditing clinical practice. Of particular importance, is the finding that the clinical presumption of disseminated breast cancer as a cause of 'terminal' illness in some patients may be misleading and dangerous, possibly denying some patients treatment of potentially remedial conditions by the institution of inappropriate terminal care.
Cytologic examination of a bronchoalveolar lavage specimen from a 6-year-old bone marrow transplant recipient revealed pulmonary infiltrates and occasional cells containing discrete pink cytoplasmic inclusions on a May-Grunwald-Giemsa stain. Direct immunofluorescence stains of cytospins prepared from the same specimen were positive for respiratory syncytial virus (RSV). Electron microscopy revealed occasional epithelial cells with cytoplasmic inclusions composed of filamentous virions. The patient died 6 months after the specimen was taken. An autopsy showed ongoing bronchiolitis with diffuse alveolar damage. Occasional bronchiolar epithelial cells contained discrete eosinophilic cytoplasmic inclusions, which on ultrastructural examination proved to be compatible with RSV. Examination of bronchoalveolar lavage fluid from bone marrow transplant recipients should include a search for cytopathic changes compatible with RSV infection. Electron microscopy can be helpful in confirming this diagnosis.
Current therapy for childhood sarcomas, particularly rhabdomyosarcomas, is a multidisciplinary effort requiring input from various specialists. Significant progress has been made in lower-stage disease because of advances in chemotherapy, radiotherapy, and surgery, but cure rates remain poor in high-stage lesions, and there is significant morbidity after treatment of lesions with a favorable outcome. Histologic classification is not always predictive of behavior, but recent modifications promise better prognostic significance. Great advances have also been made in our understanding of the biology of these lesions; these advances offer the promise of future therapeutic applicability. Detection of genetic alterations in predisposed individuals is possible but raises several significant nontherapeutic issues.
Haemorrhagic nodules have been mentioned previously as a significant cause of epistaxis in adults. We have taken photographs and obtained biopsies to characterize them. They consist of an aneurysmal dilatation of an unusually sited muscular artery with evidence of hypertensive changes in the wall, and thrombus and haemorrhage into the adjacent connective tissue.
Dystrophin, the protein product of the Duchenne muscular dystrophy locus, is a major component of the subsarcolemmal cytoskeleton in skeletal muscle cells and is a relatively muscle specific protein. We evaluated, retrospectively, the expression of dystrophin in 23 small round cell tumors of childhood including: 9 rhabdomyosarcomas, 4 neuroblastomas, 1 ganglioneuroblastoma, 2 small noncleaved cell lymphomas, 1 lymphoblastic lymphoma, 2 medulloblastomas, 2 primitive neuroectodermal tumors, 1 Wilms' tumor, and 1 undifferentiated sarcoma. Frozen sections were stained by the avidin biotin immunoperoxidase technique using a commercially available monoclonal antibody NCL-DYS1 (Novocastra) that recognizes the mid-rod domain (between amino acids 1181 and 1388) of human dystrophin. Positive controls were represented by frozen sections of normal skeletal muscle. Negative controls consisted of substituting the dystrophin antibody for normal rabbit serum. Eight of nine rhabdomyosarcomas revealed positivity whereas, none of the other tumors stained for dystrophin. This study provides evidence that monoclonal antibodies to dystrophin may be a potential useful addition to the panel of muscle markers used to diagnose small round cell tumors of childhood.
Ewing's sarcoma and the related primitive neuroectodermal tumor (PNET) share a unique and specific t(11;22)(q24;q12) chromosomal translocation. The breakpoints have recently been cloned and shown to involve the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11. Translocation results in the fusion of these genes on the der(22) chromosome, resulting in the production of a novel chimeric EWS/FLI-1 message. Using oligonucleotide primers derived from EWS and FLI-1 complementary DNAs, we were able to amplify a specific fusion transcript from 18 of 18 cases containing t(11;22) and 10 of 14 cases of Ewing's sarcoma/PNET that had unsuccessful cytogenetics. No EWS/FLI-1 fusion transcripts were detected in five cell lines derived from cases of pediatric sarcomas having a histological diagnosis other than Ewing's sarcoma/PNET. The sensitivity and specificity of this PCR analysis demonstrates the usefulness of this approach for the primary diagnosis of t(11;22)-containing Ewing's sarcoma/PNET and for the detection of metastatic or residual disease.
The frequent difficulties encountered in the diagnosis of pediatric sarcomas, caused by the lack of observable differentiation at the light microscopic level, has led to the routine use of immunohistochemistry in pediatric surgical pathology. To a large degree the advent of this staining technique has led to the correct assessment of many perplexing lesions that previously would have been given inconclusive diagnoses. However, with increased usage and testing, it has become apparent that there are few, if any, "magic bullets" in immunohistochemistry for pediatric pathologists. Thus, it behooves diagnosticians to be careful in the usage of this technique, to be aware of possible discrepancies in its results, and to remember the ancillary nature of its application. The following article will review selected markers commonly used in pediatric surgical pathology, from both previous reports and the author's perspective, and will briefly consider several new phenotypic markers which have potential utility with childhood sarcomas.
Monoclonal antibodies (MoAbs) were developed against recombinant wild-type murine MyoD1 protein. Each of 4 MoAbs was immunologically reactive with recombinant MyoD1 protein by enzyme-linked immunosorbent assay, and each specifically stained the nuclei of myogenic cells. Epitopes were mapped using fusion protein constructs with specific deletions of defined regions of the MyoD1 molecule. MoAb 5.2F recognized an epitope in the amino terminal region between amino acid residues (AAR) 3 and 56, whereas epitopes for MoAbs 1.1A, 5.4G, and 5.8A were in the carboxyl terminus (AAR 167-318) of the MyoD1 protein. The epitope for MoAb 5.8A was further delineated to AAR 170-209 by Western analysis and immunoprecipitation of in vivo transcribed and translated MyoD1 protein having specific deletions in the carboxyl terminus. The 5.8A epitope was ultimately localized to the region between AAR 180 and 189 of the protein by enzyme-linked immunosorbent assay using 10-amino acid residue synthetic peptides. This sequence is apparently unique to MyoD1 and has little homology to other myogenic regulatory proteins (myogenin, Myf5, Myf6, and MRF4). Transfection of cDNA for murine MyoD1 into a nonmuscle cell line conferred 5.8A reactivity, confirming the specificity of this reagent. MoAb 5.8A was then used to examine the expression of MyoD1 in normal and malignant human tissues. MyoD1 was not detected in any normal adult tissue but was detected in 25 of 25 histologically confirmed rhabdomyosarcomas. Staining was localized to the nucleus and showed marked heterogeneity between cells as well as differential staining within nuclei. Specific subcellular localization of 5.8A was further determined by immunoelectron microscopy, where antibody was found to localize to electron-dense areas, more frequently associated with the nuclear submembranous region. In addition to rhabdomyosarcomas, MoAb 5.8A stained 2 of 5 Wilms' tumors and one ectomesenchymoma, neoplasms known to contain myogenic elements. The 5.8A reagent was also of value in the accurate histopathological classification of 2 of 4 tumors previously diagnosed as extraosseous Ewing's sarcoma and 2 of 3 tumors diagnosed as undifferentiated sarcomas.
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Colorectal cancer is rare in patients younger than 20 years of age (incidence, 1 in 10 million). Although carcinoembryonic antigen (CEA) and carbohydrate 19-9 antigen (CA 19-9) have been used widely as markers for the efficacy of therapy or detection of recurrent colorectal carcinomas in adults, no studies evaluating their efficacy in children and adolescents have been performed. Between 1986 and 1989, serial measurements of serum CEA and CA 19-9 levels were obtained from 11 patients (aged 8 to 18 years) treated at the institution of the authors. In contrast to the experience in adults, most (9 of 11) of the tumors were localized in the right or transverse colon. Histologically, 10 of 11 carcinomas were mucinous. Most patients had either Dukes' C (5 of 11) or D (5 of 11) lesions. After surgery, all patients were treated with a combination of 5-fluorouracil with Leucovorin (Lederle Laboratories, Pearl River, NY). With the use of the adult normal standards (CEA less than 3.0 ng/ml and CA 19-9 less than 37 ng/ml)6 for the patients, the specificity and sensitivity of CEA were 77% and 64%, respectively, whereas the specificity of CA 19-9 was 79% and the sensitivity was significantly low (10%). The combined specificity of the two markers was 71%, and the combined sensitivity was 60%. On the basis of these results, the authors believe that CEA and CA 19-9 are not effective markers for detection of recurrent or progressive colorectal carcinomas in children and adolescents.
Four patients who had completed chemotherapy for malignant disease are presented. Unexpected findings of pulmonary infiltrates on chest radiographs of two patients and solitary and/or confluent nodules on CT in all four led to open lung biopsy. Histologic diagnosis in each case was bronchiolitis obliterans-organizing pneumonia (BOOP). This usually innocuous disorder can be differentiated histologically from the more severe pure bronchiolitis obliterans and should be considered in the differential diagnosis of pulmonary lesions associated with malignant disease.
In this report, we describe two rosette-forming primitive neuroectodermal tumors that were found to contain desmin by both immunohistochemistry and Western blotting. Electron microscopy on both cases was consistent with primitive neuroectodermal tumors and revealed that the tumor cells contained cytoplasmic bundles of intermediate filaments. In both cases, studies for MyoD1 protein using immunohistochemistry and Western blotting were negative. Thus, the detection of desmin in a pediatric neoplasm does not absolutely exclude the diagnosis of primitive neuroectodermal tumor and should not be considered as prima facie evidence that a small-cell tumor is a rhabdomyosarcoma.
RATIONALE AND OBJECTIVES: To improve the accuracy of magnetic resonance imaging (MRI) in evaluating the response of osteosarcomas to preoperative chemotherapy, the authors developed a technique of mapping tumor necrosis and viability by quantitating slope values of gadolinium-DTPA (Gd-DTPA) uptake on dynamic fast low-angle shot (FLASH) images. METHODS: Dynamic contrast-enhanced FLASH imaging of a single representative plane was performed on six osteosarcomas. Tumors were mapped by dividing resultant images into contiguous regions of interest and deriving slopes representing percentage increase in signal intensity (SI) per minute over the baseline for each region. The results were compared with estimations of viable tumor volume on subtracted Gd-DTPA-enhanced T1-weighted images and histologic maps of necrotic and viable tumor. RESULTS: Dynamic FLASH estimations of percent tumor necrosis using a critical slope value of 45% per minute correctly predicted histologic response to chemotherapy in all six patients. Comparison of dynamic FLASH and histologic maps showed a high degree of correlation. Static enhanced T1-weighted images overestimated the amount of residual viable tumor. CONCLUSIONS: Dynamic FLASH Gd-DTPA-enhanced mapping is a potentially useful noninvasive method of quantitating tumor response to chemotherapy.
Women with cervical smears showing borderline nuclear abnormality (BNA), or reactive changes in the form of squamous metaplasia (SM) or endocervical cell hyperplasia (ECH), were age-matched with healthy controls to determine the outcome of these conditions. No significant difference in the risk of dyskaryosis was observed in cases showing reactive changes and the controls. In contrast, there was a 23% excess of cases showing dyskaryosis in the repeat smears of cases of BNA over the controls. An odds ratio of 8.3 was obtained, showing dyskaryosis in subsequent smears after a diagnosis of BNA.
This report describes the cytological and histological features of a leiomyosarcoma of the breast. The differential diagnosis of this rare tumour is discussed. Eleven well documented cases of leiomyosarcoma of the breast have been reported previously and details of these are included in this review.
AIMS: To determine at what stage there is increased expression of transforming growth factor alpha (TGF alpha) in preneoplastic diseases of the breast and to determine if this would assist in the histological diagnosis of different intraduct epithelial proliferations. METHODS: Specimens were retrieved from the archives of 17 cases of ductal hyperplasia, six cases of atypical ductal hyperplasia and 13 cases of ductal carcinoma in situ together with 12 'normal' breast biopsy specimens. Sections were stained immunohistochemically for TGF alpha. The staining was assessed semi-quantitatively taking into account both the staining intensity and the proportion of cells stained. RESULTS: Minimal expression of TGF alpha was observed in normal breast tissue. Increased levels of expression were seen in ductal hyperplasia, atypical ductal hyperplasia, and ductal carcinoma in situ. Increased levels of expression of TGF alpha were also found in morphologically normal ducts immediately adjacent to areas of intraduct epithelial proliferation. CONCLUSION: Increased expression of TGF alpha occurs in the early stages of intraduct epithelial proliferation and will not help the histopathologist distinguish atypical ductal hyperplasia from either ductal hyperplasia or ductal carcinoma in situ. The molecular changes within a cell may precede the morphological changes observed by light microscopy thereby reflecting the biological potential of the epithelium.