Multicentric osteosarcoma: clinicopathologic and radiographic study of 56 cases.

Multicentric osteosarcoma (M-OGS) is characterized by multicentricity of osseous osteosarcomas, either synchronous or metachronous, without visceral involvement. The study's purpose was to clinicopathologically and radiographically analyze 56 cases of M-OGS (22 synchronous and 34 metachronous). The distal femur was the most common site. Histologically, all tumors were high grade. Of 22 patients with synchronous M-OGS, 16 had 3 or more simultaneous tumors; the axial skeleton was involved in 14 (64%) of 22 cases. In metachronous M-OGS, the second malignancy occurred after a median of 22 months. Treatment was surgery, chemotherapy, radiotherapy, or a combination of these. Patients with metachronous osteosarcoma had a median survival longer than did patients with synchronous tumors. Overall, 8 long-term survivors were treated by aggressive surgery with wide margins (plus chemotherapy and/or radiotherapy). M-OGS combines multiple skeletal locations of high-grade conventional osteosarcomas and has a poor prognosis. Aggressive surgery may result in improved long-term survival, particularly in patients with metachronous disease.

Primary Rosai-Dorfman disease of bone: a clinicopathologic study of 15 cases.

Sinus histiocytosis with massive lymphadenopathy or Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder of unknown etiology. Most patients present with lymph node involvement manifesting as adenopathy; however, RDD may arise primarily in a variety of extranodal sites, including bone. We report herein our experience with 15 cases of primary intraosseous RDD. The patients include 8 females and 7 males, who ranged in age from 3 to 56 (mean 27) years. The lesions arose in a variety of anatomical locations, including the tibia, femur, clavicle, skull, maxilla, calcaneus, phalanx, metacarpal, and sacrum. Radiographically, the lesions were lytic with well defined and usually sclerotic margins. Histologically, the lesions demonstrated the classic features of RDD and consisted of a mixed inflammatory infiltrate with numerous large histiocytes with abundant eosinophilic cytoplasm which exhibited emperipolesis. Some cases also contained numerous neutrophils. Immunohistochemical stains showed that the large histiocytes were S-100 positive. Follow-up information was available for 12 patients. Five patients eventually developed additional extraosseous manifestations, including testicular, lymph node, and subcutaneous lesions. One of these 5 also developed a new bony lesion within the sternum. One patient developed additional lesions within multiple bones of the hand and wrist, without extraosseous disease. One patient had stable bony lesions, whereas 5 remained disease free after treatment.

Expression of embryonic lethal abnormal vision (ELAV)-like protein HuR and cyclooxygenase-2 (COX-2) in Ewing sarcoma.

AIMS AND BACKGROUND: HuR is a member of the family of ELAV (embryonic lethal abnormal vision)-like proteins that stabilize several cellular mRNAs by binding to AU-rich elements in the 3' untranslated region of the mRNA. Cyclooxygenase-2 (COX-2) is a well known enzyme that promotes tumor growth and metastasis. Recent studies have shown that HuR can stabilize the mRNA of COX-2, and cytoplasmic expression of HuR is associated with increased COX-2 expression in some cancers. The aim of this study was to investigate the correlation between COX-2 and HuR in Ewing sarcoma. METHODS: The expression patterns for HuR and COX-2 were assessed via immunochemical analysis of 70 Ewing sarcoma samples. RESULTS: Nuclear HuR expression was observed in 12 of 70 (17.1%) cases, but cytoplasmic expression was not observed. COX-2 expression was seen in 25 of 70 (35.7%) samples. Nuclear HuR and COX-2 were simultaneously expressed in 8 of 70 (11.4%) samples. The expression of nuclear HuR was significantly associated with COX-2 expression (P = 0.014). Neither HuR nor COX-2 expression showed a correlation with age or sex. CONCLUSIONS: COX-2 expression in Ewing sarcoma may not be directly related to mRNA stabilization by HuR. However, a correlation between COX-2 expression and nuclear HuR expression through indirect mRNA stabilization can be suggested.

Incidence, prevalence, and management of intraductal papillary mucinous neoplasm in Olmsted County, Minnesota, 1984-2005: a population study.

OBJECTIVES: Intraductal mucinous papillary neoplasm (IPMN) is being recognized with increasing frequency around the world. The true incidence, however, remains unknown. Our goal was to determine the incidence of IPMN in a population study. METHODS: We used the records-linkage system of the Rochester Epidemiology Project to ascertain age- and sex-adjusted incidence rates of IPMN in Olmsted County, Minn, from January 1, 1984, to December 31, 2005. We also evaluated the number of prevalent cases as of December 31, 2005. RESULTS: We identified 28 incident cases of IPMN. The age- and sex-adjusted cumulative incidence for IPMN in Olmsted County is 2.04 cases per 100,000 persons (95% confidence interval [CI], 1.28-2.80) from 1984 to 2005. Point prevalence on December 31, 2005, was 25.96 cases per 100,000 persons (95% CI, 14.53-37.38 cases) or 1 per 3852. Restricting to county residents 60 years and older, the point prevalence is 99.10 cases per 100,000 persons (95% CI, 54.40-143.79 cases) or one per 1009 persons. Thirty-two percent of patients were treated surgically. The 5-year survival rate after diagnosis was 59.6%. CONCLUSIONS: The incidence of IPMN in Olmsted County is low but increasing. Most patients do not die of complications related to the disease.

Frequency of USP6 rearrangements in myositis ossificans, brown tumor, and cherubism: molecular cytogenetic evidence that a subset of "myositis ossificans-like lesions" are the early phases in the formation of soft-tissue aneurysmal bone cyst.

OBJECTIVE: USP6 rearrangements with several partner genes have been identified recently in primary but not in secondary aneurysmal bone cysts (ABCs). Several lesions show histologic features that may overlap with ABC, including myositis ossificans (MO), brown tumor, and cherubism. The objective of this study was to assess whether these lesions harbored USP6 rearrangements. MATERIALS AND METHODS: Twelve patients with classic radiologic and histologic features of MO, 6 with brown tumors, and 5 with cherubism diagnosed at our institution were studied for the presence of USP6 rearrangements using fluorescence in situ hybridization with probes flanking the USP6 locus on chromosome 17p13. In addition, conventional cytogenetic analysis was performed in 2 patients with cherubism. RESULTS: USP6 rearrangements were identified in 2 patients with radiologic and histologic features consistent with MO. None of the patients with brown tumor or cherubism demonstrated USP6 rearrangements. Cytogenetic analysis of the cherubism patients demonstrated normal karyotypes. CONCLUSION: These findings indicate that a subset of cases with apparent classic histologic and imaging features of MO are rather better classified as being soft-tissue ABC with clonal USP6 rearrangements. In contrast, no USP6 rearrangements were found in patients with cherubism or brown tumor, supporting the prevailing view that these lesions are distinct biologic entities.

Ameloblastic carcinoma: an analysis of 14 cases.

OBJECTIVES: To present the classifications of malignant ameloblastomas, provide histopathologic guidelines for the diagnosis of ameloblastic carcinoma, and discuss treatment and long-term follow-up. STUDY DESIGN: Fourteen archival specimens of ameloblastic carcinoma with detailed treatment and follow-up documentation were identified by the authors. RESULTS: Traditional methods of microscopic observation form the basis for diagnosis. Histopathologic features of ameloblastic carcinoma include lack of differentiation, hypercellularity, high mitotic index, vascular invasion, and neural invasion. CONCLUSION: The long-term follow-up findings in this study support the concept that aggressive surgical intervention provides the best chance for survival. Patients treated otherwise had recurrence. The patients with the highest number of recurrences did not survive the disease.

Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas.

Ewing sarcoma is a highly malignant tumor of bone preferentially arising in children and young adults. Its 5-year survival rate is only 50% despite the use of multimodal therapeutic approaches, requiring a search for new therapeutic targets and the development of novel therapeutic modalities. KIT and PDGFRs are type III receptor tyrosine kinases, and activating mutations in c-kit (which encodes KIT) and PDGFRs have been reported as oncogenic events in many malignancies. Imatinib is a selective inhibitor of KIT, PDGFR, and ABL tyrosine kinase activity and exerts different anti-tumor effects according to the regions of mutations in c-kit and PDGFR genes. Thus, we evaluated the immunohistochemical expression of KIT protein and the mutational status of exons 9, 11, 13, and 17 of the c-kit gene, exons 12 and 18 of the PDGFRA gene, and exon 12 of the PDGFRB gene in 71 formalin-fixed, paraffin-embedded Ewing sarcomas to increase our understanding of the potential, if any, of imatinib treatment for this malignancy. Of the 71 samples, 27 (38%) were immunohistochemically positive for KIT; however, activating mutations in c-kit were found in only 2 of 71 Ewing sarcomas (2.6%) within exon 9. No activating mutations in the PDGFRA and PDGFRB genes were found, but pleomorphism was identified in exon 18 of the PDGFRA gene. Our results for KIT protein expression agree with those of previous studies. This is the largest series of c-kit mutational analysis in Ewing sarcoma to date, and the results definitively show that c-kit activating mutations are not coincident with KIT protein expression in Ewing sarcoma in most samples. These findings imply other mechanisms for KIT activity and leave open the question of whether imatinib would be efficacious in the treatment of Ewing sarcoma.

Intraoperative diagnosis of isolated cardiac sarcoid.

Cardiac sarcoid is a rare and frequently fatal disease. We report a case of isolated cardiac sarcoid diagnosed during elective cardiac surgery. Although this patient presented with a history that was consistent with sarcoid heart disease, diagnosis is challenging when there is no other organ involvement with sarcoid. The patient was successfully treated with steroids and 8 years later remains clinically free of sarcoidosis.

Periosteal osteoblastoma: report of a case with a rare histopathologic presentation and review of the literature.

Osteoblastoma is an uncommon benign bone tumor most commonly located in the vertebral column or metaphysis of a long bone. Periosteal location is rare. We report a periosteal-based osteoblastoma, arising from the proximal tibia, in a 20-year-old woman who presented with knee swelling and pain of 2-year duration. Imaging studies showed a metaphyseal surface-based lesion with patchy radiodensities. The cortico-medullary junction was intact. The lesion was totally excised. Histopathologic evaluation disclosed immature bone and osteoid deposition in a vascularized stroma, associated with numerous osteoblasts and osteoclasts rimming the bony trabeculae. Plate-like arrangements of cartilage in the margin of the neoplastic tissue were also identified. At 16 months postoperatively, the patient was well without recurrence. Although extremely unusual, the presence of cartilage does not necessarily exclude the diagnosis of osteoblastoma.

Follow-up study of long-term survivors of osteosarcoma in the prechemotherapy era.

Osteosarcoma is the most common primary bone sarcoma. Several studies published in the 1960s established that approximately one fifth of patients survive when treated with surgery alone. There is no information, however, about the long-term consequences of osteosarcoma. It is especially relevant to know if these patients are at risk for a second malignancy. We reviewed all clinical records from long-term (defined as more than 10 years) osteosarcoma survivors treated at Mayo Clinic in the prechemotherapeutic era from 1900 to 1960. We re-reviewed histological sections for most cases. Patients or next of kin provided follow-up information during telephone interviews. Rates of second malignancy were compared with expected rates in the population at large. We identified 465 patients treated for osteosarcoma. Of these patients, 83 (17.8%) were long-term survivors, including 19 who were alive up to 65 years after treatment. Of the 7 patients with pulmonary metastases, 3 died. A second malignancy developed in 26 patients, 15 of whom died of the malignancy. Although long-term survivors of osteosarcoma have a higher incidence of a second malignant tumor than a normal population, this increase was not statistically significant. No demographic or histological variables predicted long-term survival.

Upregulation of the oncogenic helix-loop-helix protein Id2 in Ewing sarcoma.

AIMS AND BACKGROUND: Id helix-loop-helix proteins function as regulators of cell growth and differentiation. However, they can induce malignant transformation when overexpressed. The EWS/ETS chimeric proteins in Ewing sarcoma act as aberrant transcription factors leading to tumorigenic processes. An enhanced expression of the Id2 gene in Ewing sarcoma cells was previously shown by gene array techniques. We investigated the expression of Id2 at the protein and gene level in Ewing sarcoma. METHODS: We evaluated the expression of Id2 protein using immunohistochemistry in formalin-fixed, paraffin-embedded specimens from a total of 71 cases of Ewing sarcoma. Additionally, a Ewing sarcoma cell line was examined by real-time quantitative PCR. RESULTS: Id2 expression was observed in 65 cases (91.5%) of the 71 total cases examined and a high level of Id2 expression was observed in 45 of these cases (63.8%). In tumor cells, Id2 proteins displayed cytoplasmic as well as nuclear localization. The amplification of the Id2 gene was not noted in a Ewing sarcoma cell line using real-time quantitative PCR. The crossing points of Id2 in the Ewing sarcoma cell line, control fibroblast, and osteosarcoma cell line were 18.54 +/- 0.16, 18.25, and 18.34, respectively. CONCLUSIONS: Our data support a role for increased Id2 protein expression in Ewing sarcoma. However, this overexpression of the Id2 protein could not be confirmed by a corresponding change at the gene level in a Ewing sarcoma cell line.

Intraabdominal myositis ossificans: a report of 9 new cases.

Intraabdominal myositis ossificans (IMO) is a rare benign disorder characterized by reactive bone formation in intraabdominal soft tissue that should be distinguished from a malignant condition. We retrospectively searched our patient records and report 9 new cases of IMO. The lesions occurred in 7 men and 2 women with a mean age of 50 years (range, 24--76 years), 5 of whom had previous abdominal surgery. Histologically, all the cases were similar, consisting of a reactive mesenchymal process in adipose tissue. Mitosis was observed, but with no atypical forms, and the lesions lacked malignant cytologic features. IMO is an uncommon benign lesion that develops relatively rapidly. The pathogenesis is related to intraabdominal surgical procedures, but the exact mechanism remains to be determined.

Radiographic, CT, and MR imaging features of dedifferentiated chondrosarcomas: a retrospective review of 174 de novo cases.

Up to 11% of chondrosarcomas may undergo regional anaplastic change, resulting in a high-grade noncartilaginous sarcoma arising within a typically low-grade chondrosarcoma. Known as dedifferentiated chondrosarcomas, these tumors are highly malignant with a very poor prognosis. The most important factor affecting survival is an accurate preoperative diagnosis. Therefore, the ability to predict the possibility of dedifferentiation in a malignant cartilage tumor on the basis of imaging findings is critical to ensure adequate tumor sampling at the time of biopsy. Imaging findings at radiography, computed tomography (CT), and magnetic resonance (MR) imaging in 174 patients with dedifferentiated chondrosarcoma were reviewed to determine whether there are radiologic features that can help predict dedifferentiation. On approximately one-third of the radiographs, one-third of the MR images, and one-half of the CT scans, the tumors demonstrated bimorphic features (ie, distinctly different tumor features juxtaposed within the lesion), most frequently a dominant lytic area adjacent to a mineralized tumor at radiography and a large, unmineralized soft-tissue mass associated with an intraosseous chondroid-containing tumor at CT and MR imaging. In the initial evaluation of patients with a primary bone tumor, thorough evaluation of the radiologic features of the entire tumor is critical.

Primary Ewing's sarcoma of the vertebral column.

OBJECTIVE: To determine the demographics, imaging findings, clinical symptoms, and prognosis of primary vertebral Ewing's sarcoma (PVES). DESIGN: A retrospective review of medical records and radiological studies of patients diagnosed with PVES from 1936 through 2001 in our institution and Department of Pathology consultation files was undertaken. Metastatic and soft tissue Ewing's sarcoma cases were excluded. RESULTS: From a total of 1,277 cases of Ewing's sarcoma, 125 (9.8%) had a primary vertebral origin. There were 48 females and 76 males. Patient ages ranged from 4 to 54 (mean 19.3, standard deviation 10.7, median 16) years. Vertebral column distribution was four cervical (3.2%), 13 thoracic (10.5%), 31 lumbar (25%), and 67 sacrum (53.2%). More than one vertebral segment was involved in ten cases (8%). Satisfactory imaging studies were available in 51 patients: 49 radiographs, 27 computerized tomography (CT), and 23 magnetic resonance imaging (MRI) studies. The majority of tumors were lytic (93%). Three cases were mixed lytic and sclerotic (6%) and one sclerotic. In the nonsacral spine, the majority of lesions (12/20) involved the posterior elements with extension into the vertebral body. Five cases were centered in the vertebral body with extension into the posterior elements. Two cases were limited to the posterior elements, and one case solely involved the vertebral body. Ala was the most frequently affected site in the sacrum (18/26). Spinal canal invasion was frequent (91%). Detailed clinical information was available in 53 patients. Duration of symptoms ranged from 1 to 30 (mean 7) months. Local pain was the first symptom and seen in all cases. Neurological deficits were present in 21 (40%) cases. All patients received radiation in various dosages; 70% additionally received chemotherapy. Twenty-five patients had surgery, and two patients received bone marrow transplantation. Forty-five patients had follow-up; the five-year disease-free survival probability is 0.53. Disease-free survival probabilities are 0.60 for sacral tumors and 0.45 for nonsacral tumors. CONCLUSION: PVES is an uncommon tumor, usually seen in the second decade of life (mean age 19.3 years) with a male predilection (62%). An aggressive osteolytic lesion, particularly in the sacrum, should raise suspicion for this tumor in adolescents. Prognosis was similar in sacral and nonsacral tumors.

Imaging features of low-grade central osteosarcoma of the long bones and pelvis.

PURPOSE: To determine the age and gender distribution and imaging features of low-grade central osteosarcoma (LGCOS) of the long bones and pelvis and to discuss our findings in the context of lesions for which LGCOS has been mistaken. MATERIALS AND METHODS: We reviewed 99 cases of LGCOS collected between 1919 and 2002 from our institution and pathology consultation files. Adequate imaging was available in 70 cases (36 radiographs only, 17 radiographs/CT, 12 radiographs/MRI, 2 radiographs/CT/MRI, 2 CT only, 1 MRI only, 5 bone scans). RESULTS: Patient average age was 30.1+/-14.2 years, with a slight female predominance. The femur and tibia were the most common long bones involved (29 and 20 each) with the majority of these tumors arising around the knee, followed by the fibula, radius, humerus and ulna (four, three, two and one case each). Flat bones were involved in six cases (three pelvis, one rib, two scapulae). Short tubular bones were involved in five cases (two metatarsal, two phalanges, one clavicle). The lesion extended to the end of the affected long bone in 22 of 59 cases. Lesions were large at presentation (mean 7.9+/-4.6 cm, range 2-24). Four radiographic patterns were identified: lytic with varying amounts of thick and coarse trabeculation ( n=22), predominantly lytic with few thin, incomplete trabecula ( n=21), densely sclerotic ( n=17) and mixed lytic and sclerotic ( n=10). Lesions were benign-appearing overall with focally aggressive features. CT or MRI demonstrated cortical breech or extension into the soft tissues in all cases. CONCLUSIONS: LGCOS has a variable appearance on radiographs. A frequent pattern is a slow-growing large intracompartmental fibro-osseous lesion with varying amounts of septal ossification associated with focal areas of aggression. A homogeneously sclerotic pattern was also noted. Imaging with CT or MRI was helpful in every instance in our series in identifying areas of soft tissue extension or cortical disruption suggestive of a low-grade malignancy.