Osteolytic lesions (brown tumors) of primary hyperparathyroidism misdiagnosed as multifocal giant cell tumor of the distal ulna and radius: a case report.

BACKGROUND: Brown tumors represent a rare clinical manifestation reported in approximately 3% of patients with primary hyperparathyroidism and correspond to radiologically osteolytic lesions with well-defined borders in different parts of the skeleton. CASE PRESENTATION: We report the case of a 53-year-old white man who presented to our hospital with osteolytic lesions of his distal ulna and radius, causing pain and swelling of 2-month duration. A subsequent biopsy revealed histological features consistent with giant cell tumor and a complete resection of his distal ulna was followed, along with curettage and cementoplasty of the distal radial metaphysis. Two weeks later, he was re-admitted with diffuse musculoskeletal soreness, anorexia, constipation, nausea, and localized abdominal pain and multiple osteolytic lesions on plain radiographs. A histopathological examination of the ulna and radius specimens showed similar findings and, given the multifocality, brown tumors related to primary or secondary hyperparathyroidism was included in the differential diagnosis. A laboratory examination showed high total serum calcium (14.5 mg/dl) and low serum phosphorus and 25-hydroxyvitamin D levels. Primary hyperparathyroidism was suspected and confirmed by the elevated parathyroid hormone levels of 1453 pg/mL. At radiological work-up, using computed tomography, ultrasonography, and parathyroid subtraction technetium-99m sestamibi scintigraphy, a 4.5 × 2.5 × 3.2 cm mass emanating from the right lobe of his thyroid gland was detected, displaying extensive uptake in the right lower parathyroid gland. After appropriate medical support including hyperhydration and high doses of diuretics and diphosphonates, his laboratory profile normalized and he underwent total thyroidectomy with removal of the parathyroid glands. Our patient is now recovering 12 months after surgery, with normal values of serum parathyroid hormone and calcium levels. The lytic bone lesions have almost disappeared and no other additional orthopedic intervention was necessary. CONCLUSIONS: The present case report emphasizes the need of inclusion of brown tumors in the differential diagnosis of multifocal osteolytic bone lesions, in order to avoid harmful surgical interventions. Laboratory testing of serum phosphate, calcium levels, and parathyroid hormone levels should always be included in the routine survey of patients with multifocal osteolytic lesions.

Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.

Fallopian tube malignant mixed müllerian tumor (carcinosarcoma): a case report with immunohistochemical profiling.

We report a case of malignant mixed müllerian tumor (MMMT) (carcinosarcoma) of the right fallopian tube in a 69-year-old woman presenting with abdominal pain and an adnexal mass. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, received adjuvant chemotherapy and is without evidence of disease 12 months postoperatively. The tumor involved the fallopian tube and was composed of in situ and invasive high-grade serous and undifferentiated carcinoma, leiomyosarcoma, rhabdomyosarcoma and undifferentiated sarcoma. Immunohistochemically, the epithelial and mesenchymal cells expressed CD56, Leu-7 and p53. The epithelial elements expressed nuclear WT1 and calretinin while the mesenchymal cells showed negative nuclear and strong cytoplasmic staining. HBME was observed focally in carcinoma. The expression of mesothelial-associated antigens WT1, calretinin and HBME in MMMT likely reflects the common embryologic derivation of the mesothelium and urogenital ridge. Loss of nuclear WT1 expression in the mesenchymal component may be involved in MMMT tumorigenesis.

Expression of the cell cycle regulatory proteins p34cdc2, p21waf1, and p53 in node negative invasive ductal breast carcinoma.

AIMS: To look for correlations between expression of cell cycle regulatory proteins p34(cdc2), p21(WAF1), and p53 in node negative invasive ductal breast carcinoma, or between these proteins and clinicopathological parameters, and to assess their prognostic value. METHODS: Immunohistochemistry using formalin fixed, paraffin wax embedded sections from 94 breast carcinomas. Adjacent benign epithelial breast tissue was available in 74 cases. Median follow up was 72 months. RESULTS: Nuclear and cytoplasmic p34(cdc2) expression was seen in 80 and 62 tumours, respectively; nuclear expression was seen in adjacent benign epithelium in 12 cases. p21(WAF1) and p53 were positive in 48 and 21 tumours, respectively. High expression of p34(cdc2) in neoplastic nuclei was associated with higher histological grade and p53 expression, but not with tumour size, steroid receptor status, patient age, menopausal status, recurrence, metastasis, disease free survival (DFS), or overall survival (OS). p34(cdc2) in tumour cytoplasm was associated with p34(cdc2) nuclear positivity, high tumour grade, and DFS in univariate but not multivariate analysis. In contrast, p34(cdc2) expression in benign tissue independently predicted DFS and OS in univariate and multivariate analysis. Expression of p53 was associated with high tumour grade and negative steroid receptors, but not with recurrence, metastasis, DFS, or OS. p21(WAF1) expression was not associated with the examined parameters. CONCLUSIONS: p34(cdc2), p21(WAF1), and p53 expression does not predict outcome in node negative breast carcinoma, although p34(cdc2) expression in benign tissue is related to prognosis. The association between p34(cdc2) and p53 implicates p53 in G2-M cell cycle checkpoint control, possibly via mediators unrelated to p21(WAF1).

Vascular injury complicating lumbar disc surgery. A systematic review.

OBJECTIVES: to review the literature concerning the early and late vascular complications of lumbar disc surgery. METHODS: using the MEDLINE database, we reviewed all reports of vascular complications associated with surgical excision of a prolapsed disc via a posterior approach reported in the English literature since 1965. RESULTS: we identified 98 cases of vascular complications for an incidence of 1-5 in 10000 disc operations. Early presentation is shock due to rupture of a large retroperitoneal vessel. Late complications include development of pseudoaneurysms and arteriovenous fistulas. Treatment of a vascular tear consisted mainly of primary suturing of the injured vessel. The preferred method for arteriovenous fistula and pseudoaneurysm repair was suturing from within the arterial lumen along with interposition grafting. Recently, endovascular techniques have been recommended, lowering the high morbidity and mortality related to conventional repair. CONCLUSION: iatrogenic vascular injury during lumbar disc surgery, although rare, should be suspected if signs of circulatory instability are noted or if lumbar pain, leg oedema or high output cardiac failure develop months to years following such surgical procedures. However, these symptoms may arise during or immediately after surgery, requiring immediate intervention.

Bronchial carcinoid of an accessory tracheal bronchus.

We present a rare case of bronchial carcinoid tumor arising in an accessory right tracheal bronchus and involving the associated tracheal lobe in a 48-year-old man, who presented with a history of recurrent respiratory infections and recent onset of hemoptysis. Diagnosis was established on preoperative bronchoscopy and biopsy. The tumor was completely removed by right upper lobectomy with the tracheal bronchus resected flush to its origin from the right lower tracheal wall. Final histology revealed a typical carcinoid tumor.

Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas.

The INK4A gene, a candidate tumor suppressor gene located on chromosome 9p21, encodes two protein products, p16 and p19(ARF). p16 is a negative cell cycle regulator capable of arresting cells in the G1 phase by inhibiting cyclin-dependent kinases 4 (Cdk4) and 6 (Cdk6), thus preventing pRB phosphorylation. p19(ARF) prevents Mdm2-mediated neutralization of p53. Loss of INK4A is a frequent molecular alteration involved in the genesis of several neoplasms, including tumors of neuroectodermal origin. This study investigated the frequency of INK4A gene alterations in a series of malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). INK4A gene and the p19(ARF)-specific exon 1beta were studied in 11 MPNST samples from 8 patients and 7 neurofibromas. Presence of INK4A deletions was assessed by Southern blotting hybridization and by a multiplex polymerase chain reaction (mPCR). INK4A point mutations were examined by single-strand conformation polymorphism (SSCP) and sequencing. The p16 promoter methylation status was determined by PCR amplification of bisulfite-treated DNA. Homozygous deletions of exon 2, thus affecting both p16 and p19(ARF), were identified in MPNSTs from 4 of 8 patients. Deletions, mutations, or silencing by methylation were not identified in the neurofibromas analyzed. Based on our results, we conclude that INK4A deletions are frequent events in MPNSTs and may participate in tumor progression. Silencing of p16 by methylation, which occurs often in several tumor types, is uncommon in MPNSTs.

Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas.

There is little information regarding the status of cell cycle regulators in malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). In this study, we investigated patterns of expression of p53 and pRB, cyclin-dependent kinase inhibitors (CKIs) p21 and p27, as well as cyclins D1 and E, in a cohort of 35 well-characterized MPNSTs and 16 NFs. These phenotypes were correlated with proliferative index, as assessed by Ki-67, as well as clinicopathological parameters of poor outcome. p53 nuclear overexpression was found in 10 of 35 (29%) MPNSTs, and it was lacking in NFs (P = 0.02). There were no differences in the patterns of expression of pRB, cyclin D1, and p21 between MPNSTs and NFs. However, p27 nuclear expression was present in most NFs, but it was absent in the majority of MPNSTs, which displayed cytoplasmic staining (P < 0.001). Nuclear cyclin E expression was more pronounced in MPNSTs than in NFs. We observed inverse patterns of expression for nuclear p27 and nuclear cyclin E expression. The staining profiles of cytoplasmic p27 and nuclear cyclin E expression were found to be statistically associated (P = 0.01). High Ki-67 expression was found in 20 of 34 (59%) MPNSTs but was absent in NFs (P < 0.001). Furthermore, detection of cytoplasmic p27 expression was found to be a prognostic factor for poor survival in MPNSTs (P = 0.03, relative risk = 2.4).

Improved detection of CD5 epitope in formalin-fixed paraffin-embedded sections of benign and neoplastic lymphoid tissues by using biotinylated tyramine enhancement after antigen retrieval.

To evaluate the effectiveness of the immunohistochemical staining of B- and T-cell lymphomas with Leu-1 (clone L17F12 CD5 antibody, Becton Dickinson, San Jose, Calif) in formalin-fixed paraffin-embedded sections, we stained 12 specimens reflecting cases of chronic lymphocytic leukemia/small lymphocytic lymphoma, 7 of mantle cell lymphoma, 13 of T-cell lymphomas, and 9 of various B-cell neoplasms that do not ordinarily express CD5, using a streptavidin-horseradish peroxidase method with biotinylated tyramine enhancement after antigen retrieval. We were able to detect CD5 reactivity of neoplastic cells in 9 (75%) of 12 cases of chronic lymphocytic leukemia, 6 (86%) of 7 cases of mantle cell lymphoma, and 13 (100%) of 13 of the T-cell lymphomas. B-cell neoplasms (9/9) not typically associated with CD5 expression showed no reactivity of tumor cells. We conclude that the Leu-1 (CD5) antibody, routinely used for cryopreserved tissues, is also effective in formalin-fixed paraffin-embedded sections using an antigen retrieval and streptavidin-horseradish peroxidase method with biotinylated tyramine.

Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors: a clinicopathologic study of 25 patients and 26 tumors.

BACKGROUND: To determine the effects of anatomic site on the presentation and diagnosis of malignant peripheral nerve sheath tumors (MPNSTs) and on the treatment and outcomes of the patients, the authors initiated a study of these tumors at different sites. An earlier report described MPNSTs of the buttock and lower extremity, and the current series analyzes those presenting at intrathoracic (IT) and subdiaphragmatic (SD) paraspinal sites. METHODS: The authors reviewed data on patients with paraspinal MPNSTs who were seen at Memorial Hospital during the period 1960-1995 and for whom histologic slides were available. Various clinicopathologic parameters and their effects on patient outcomes were examined. RESULTS: Twenty-five patients with 26 tumors were evaluated. Seven tumors were IT and 19 were SD; 60% of the patients had neurofibromatosis type 1 (NF1). Most patients presented with pain, and a diagnostic delay (of 3 months to 2 years) was often noted. Mean tumor sizes for SD and IT tumors were 14.3 cm and 6.6 cm, respectively. Most MPNSTs were composed of spindle cells in fascicles. Twenty-seven percent exhibited divergent differentiation. Twenty-four tumors were high grade, and a low grade component was identified in 8 tumors. Surgical resection was attempted for 23 tumors (88%), but complete resection was achieved in only 6 cases (23%). Eighty percent of the patients died of their tumors, 2-year and 5-year survival rates were 35% and 16%, and median survival was 8.5 months. Significant prognostic factors were tumor size <5 cm, the presence of a low grade component, and complete tumor resection. CONCLUSIONS: Paraspinal MPNSTs have more aggressive behavior than peripherally located tumors, mainly because of the difficulty encountered in resecting them completely. Prognoses of patients with MPNST at this site appear to be affected by resection status, tumor size, and tumor grade.

Use of a bioabsorbable polymer for the delivery of ofloxacin during experimental osteomyelitis treatment.

This study was performed to investigate the potential utility of ofloxacin-impregnated bioabsorbable polymers for osteomyelitis therapy. Pseudomonas aeruginosa osteomyelitis was induced in 48 New Zealand White rabbits. Four weeks after infection, the animals were randomized to one of four treatment groups: drug-free polymer, ofloxacin polymer, systemic ofloxacin, or ofloxacin polymer plus systemic ofloxacin. Twenty-eight days later, radiographs were taken of the affected area, the animals were killed, and bone was obtained for histologic evaluation, culture, and determination of ofloxacin concentrations. The percentage of sterile bone cultures was 33, 83, 75, and 91 for the groups treated with drug-free polymer, ofloxacin polymer, systemic ofloxacin, and ofloxacin polymer plus systemic ofloxacin, respectively. When compared with the drug-free polymer, both the ofloxacin polymer and the ofloxacin polymer plus systemic ofloxacin significantly improved the rate of sterilization. The mean concentrations of the drug in bone for the groups treated with ofloxacin polymer, systemic ofloxacin, and ofloxacin polymer plus systemic ofloxacin were 34.9 (range: 2-160), 1.9 (range: 0.8-3), and 26.0 microg/g (range: 9-100 microg/g), respectively. These data suggest that the DL-lactide:glycolide polymer studied is a suitable vehicle for the delivery of high local concentrations of ofloxacin and that these concentrations result in eradication of the bacterial pathogen in this rabbit model.

Prophylaxis of acute osteomyelitis with absorbable ofloxacin-impregnated beads.

We investigated the use of an ofloxacin-impregnated bioabsorbable composite for the prevention of acute Staphylococcus aureus osteomyelitis. New Zealand White rabbits were anesthetized, the femur was exposed, and a cortical hole was drilled. Animals were randomly given drug-free composites or ofloxacin-impregnated composites; the composites were placed at the site of injury, and the incision was closed. One hour later, all animals were intravenously inoculated with 5 x 10(4) CFU of S. aureus and observed for 28 days. Bone culture data revealed that S. aureus was isolated from 3 of 12 rabbits in the ofloxacin composite group and 9 of 11 animals in the control group (P = 0.02). Radiographic evaluation revealed that the drug-free group had a significantly (P = 0.01) greater degree of radiographic evidence of infection than the group given ofloxacin composites. Although a limited number of histologic samples were available, these data also paralleled the radiographic and culture data. This study demonstrates the effectiveness of the implantable ofloxacin bioabsorbable composites to prevent the development of acute osteomyelitis.

Age-stratified incidence of unsuspected mammary carcinoma in women with fibroadenoma.

Fibroadenomas (FA) are benign neoplasms with a known albeit rare association with mammary carcinoma (MC). Incompletely explored, however, are 1) the statistical relationship of associated FA/MC with patient age and 2) the microscopic spatial relationship of associated FA/ MC. Pathology records of 1,715 patients with FA, excised over a nine-year period, were reviewed. In 59 patients concomitant diagnoses of FA and MC were rendered. In 40 of these patients MC was clinically unsuspected, signs and symptoms being attributable to the FA. Data were age stratified and slides were reviewed to identify the precise histologic association of FA and MC. Women aged 50 years and older had a statistically significant increased association of FA and MC as compared to their younger counterparts (4.1% vs 1.5%; P = .003). MC complicating FA was in situ or invasive (82.5% vs 17.5%), of ductal, lobular, or combined type (40% vs 52.5% vs 7.5%), and half of the MC were restricted to the "normal" mammary tissue surrounding the FA.

Malignant mixed mesodermal tumors of the ovary.

OBJECTIVE: To review the experience at Women & Infants Hospital and Hartford Hospital of patients with malignant mixed mesodermal tumors of the ovary, and to review the pertinent literature. METHODS: Fourteen cases of malignant mixed mesodermal tumors of the ovary at the two hospitals over a 5-year period were identified through their tumor registries. Demographic data, pathology, treatment, and survival rates were reviewed. RESULTS: The median survival of the patients in our series was 7 months, with 64% dead of disease in 1 year. A review of the pertinent literature indicated median survivals of 6-12 months, with more than 70% of the patients dead of disease at 1 year, despite treatment. CONCLUSION: Further investigation is needed to determine the proper management for malignant mixed mesodermal tumors of the ovary. Meanwhile, current treatment strategies should recognize the present therapeutic limitations, so as not to diminish any further the quality of life for women with this malignancy.