Benjamin Hoch

Base of skull chordomas in children and adolescents : A clinicopathologic study of 73 cases

Chordomas in children and adolescents comprise <5% of all chordomas and most frequently develop in the skull base. These tumors are believed to behave more aggressively than chordomas in adults and may have unusual morphology. This study examines a large series of pediatric skull base chordomas treated with a standardized protocol to characterize the behavior and morphology of these tumors. There were 31 males and 42 females ranging from 1 to 18 (mean 9.7) years. Forty-two cases (58%) were conventional chordomas, some of which had unusual histopathologic features. Chondroid chordomas comprised 23% of cases. Fourteen tumors (19%) were highly cellular and had a solid growth pattern with no myxoid matrix or lobular architecture. Eight of these had cytologic features of conventional chordoma cells including physaliferous cells (cellular chordoma). The remaining cellular tumors were composed of poorly differentiated epithelioid cells set in a fibrous stroma and lacked physaliferous cells (poorly differentiated chordoma). All variants studied by immunohistochemistry showed positive staining for cytokeratin, epithelial membrane antigen, S100 protein, and vimentin. Mitoses and necrosis were seen in all variants. Follow-up data were available for all patients and ranged from 1 to 21 (mean 7.25) years. The survival rate was 81%. All but 1 patient with poorly differentiated chordoma died of disease. Overall, base of skull chordomas in children and adolescents treated with proton beam radiation have better survival than chordomas in adults. However, poorly differentiated chordomas are highly aggressive tumors.

Lymphotoxin β receptor signaling is required for inflammatory lymphangiogenesis in the thyroid

Infiltration of lymphocytes into the thyroid gland and formation of lymph node-like structures is a hallmark of Hashimotos thyroiditis. Here we demonstrate that lymphatic vessels are present within these infiltrates. Mice overexpressing the chemokine CCL21 in the thyroid (TGCCL21 mice) developed similar lymphoid infiltrates and lymphatic vessels. TGCCL21 mice lacking mature T and B cells (RAGTGCCL21 mice) did not have cellular infiltrates or increased number of lymphatic vessels compared with controls. Transfer of CD3+CD4+ T cells into RAGTGCCL21 mice promoted the development of LYVE-1+podoplanin+Prox-1+ vessels in the thyroid. Genetic deletion of lymphotoxin β receptor or lymphotoxin α abrogated development of lymphatic vessels in the inflamed areas in the thyroid but did not affect development of neighboring lymphatics. These results define a model for the study of inflammatory lymphangiogenesis in the thyroid and implicate lymphotoxin β receptor signaling in this process.

Multicentric giant cell tumor of bone. Clinicopathologic analysis of thirty cases.

BACKGROUND Giant cell tumor of bone accounts for 4% to 5% of primary bone tumors. Approximately 1% of cases present as multiple synchronous or metachronous lesions. In this study, we describe the clinicopathologic features of thirty cases of multicentric giant cell tumor. METHODS Thirty patients who had two or more separate lesions that had been pathologically confirmed to be giant cell tumors were identified. Radiographs were reviewed to evaluate the characteristics and locations of the tumors. Histologic reexamination was performed to document morphologic features. Clinical information and follow-up data were obtained from the medical records. RESULTS The male:female ratio was 1:2, with an average age at presentation of twenty-one years. Fifty-nine percent of the patients were younger than twenty years of age. There were ninety-four tumors in the series, with an average of three (range, two to nine) per patient. Most tumors had arisen in the long bones. Six patients had synchronous ipsilateral involvement of the distal part of the femur and the proximal part of the tibia. Radiographically, the tumors in long bones manifested as expansive lytic lesions involving the metaphysis and extending into the epiphysis. A minority of the tumors were confined to the metaphysis, had features of a fibro-osseous or bone-forming lesion, or arose in skeletally immature patients. Secondary histopathologic changes including fibrohistiocytic regions, reactive bone formation, or aneurysmal bone cyst-like changes were not uncommon. Most tumors were treated with curettage (64%) or resection (22%). The recurrence rate was similar to that of solitary giant cell tumors. Metastatic disease developed in three patients, and two patients had malignant transformation. CONCLUSIONS Multicentric giant cell tumors occur more often in younger patients than do solitary giant cell tumors, and they frequently present as synchronous lesions around the knee. Some tumors appear as bone-forming or fibro-osseous tumors on imaging studies as a result of fibrohistiocytic regions and reactive bone formation. The risk of recurrence depends on the type of surgery that is performed. LEVEL OF EVIDENCE Therapeutic Level IV.

Correlation of Positron Emission Tomography Standard Uptake Value and Pathologic Specimen Size in Cancer of the Head and Neck

PURPOSE To correlate positron emission tomography (PET) standard uptake value (SUV) with pathologic specimen size in patients with head-and-neck cancers. METHODS AND MATERIALS Eighteen patients with Stage II-IVB head-and-neck cancer with 27 tumors who underwent PET and computed tomography (CT) imaging of the head and neck followed by surgical resection were selected for this study. Various SUV thresholds were examined, including the software default (SUV(def)), narrowing the window by 1 standard deviation (SD) of the maximum (SUV-1SD), and SUV cutoff values of 2.5 or greater (SUV2.5) and 40% or greater maximum (SUV40). Volumetric pathologic data were available for 12 patients. Tumor volumes based on pathologic examination (gold standard), CT, SUV(def), SUV-1SD, SUV2.5, and SUV40 were analyzed. RESULTS PET identified five tumors not seen on CT. The sensitivity of PET for identifying primary tumors was 94% (17 of 18). The Sensitivity of PET for staging the neck was 90% (9 of 10), whereas the specificity was 78% (7 of 9). The SUV2.5 method was most likely to overestimate tumor volume, whereas SUV(def) and SUV-1SD were most likely to underestimate tumor volume. CONCLUSIONS The PET scan provides more accurate staging of primary tumors and nodal metastases for patients with advanced head-and-neck cancer than CT alone. Compared with the gold standard, significant variability exists in volumes obtained by using various SUV thresholds. A combination of clinical, CT, and PET data should continue to be used for optimal treatment planning. The SUV40 method appears to offer the best compromise between accuracy and reducing the risk of underestimating tumor extent.

Synovial chondromatosis of the lumbar spine with compressive myelopathy: a case report with review of the literature

Synovial chondromatosis has been rarely reported to occur in the spine with only one case found in the lumbar spine. We describe another case of synovial chondromatosis in the lumbar spine in a 41-year-old man who presented with compressive myelopathy. The tumor was located in the left ventrolateral corner of the epidural space just below the L4–L5 intervertebral space. Besides being extremely rare, our case was unusual in that the juxtaposed facet joint was radiologically normal.

Demineralized bone matrix and fat autograft in a rabbit model of frontal sinus obliteration

OBJECTIVE: In this study, we investigate the efficacy of demineralized bone matrix (DBM) as a material for frontal sinus obliteration in a rabbit model. STUDY DESIGN AND SETTING: Twenty-four New Zealand White rabbits were divided into four groups, and the study was carried out to two time periods. Twelve rabbits underwent frontal sinus obliteration with fat autograft, and 12 rabbits underwent the procedure with DBM. At 12 weeks, six control and six study rabbits were killed. The remaining 12 rabbits were killed at 36 weeks. All specimens underwent radiologic evaluation with spiral CT followed by histologic examination for evidence of bony growth. RESULTS: Sinuses obliterated with DBM showed replacement of the sinus cavity by trabecular bone. Histology demonstrated significant progressive replacement of DBM by cancellous bone from 12 weeks (53.3%) to 36 weeks (78.8%). There were no complications observed as a result of the materials used. CONCLUSION AND SIGNIFICANCE: DBM is a prospective material for frontal sinus obliteration. Long-term studies and human trials will further elucidate the role of this material.

Comparison of fast-setting calcium phosphate bone cement and fat autograft in a rabbit model of frontal sinus obliteration.

Background Traditionally, chronic obstruction of the frontal recess is managed by frontal sinus obliteration (FSO). This often requires the harvest of abdominal fat as a filler with all of its associated morbidity. In this study, we investigate the efficacy of calcium phosphate bone cement (Craniofacial Repair System [CRS]) as a material for FSO. Methods Eighteen New Zealand white rabbits were divided into three groups and carried out to two time periods. Six rabbits underwent FSO with fat autograft (control group) and 12 rabbits underwent FSO with CRS (study groups 1 and 2, respectively). At 52 weeks, six control and six study rabbits were killed. The remaining six rabbits were killed at 78 weeks. All specimens underwent radiological evaluation with spiral computed tomography (CT) followed by gross inspection. Histological evaluation was then performed to assess bony growth and to evaluate the interface of the sinus wall with the obliterative material. Results Sinuses obliterated with CRS showed complete obliteration radiographically. This was apparent at 52 weeks and remained static at 78 weeks. Histological analysis indicated persistent obliteration of the sinus cavity from 52 to 78 weeks and signs of osteoinduction. There were no complications observed as a result of the operative procedure or the materials used. Conclusion CRS is an alternative to fat autograft for FSO in this noninfected animal model. Further studies are needed to evaluate its long-term efficacy as well as its behavior in chronically infected sinuses.

Primary periosteal lymphoma—rare and unusual

We describe a primary periosteal lymphoma that involved only the periosteum without affecting the adjacent medulla or the regional lymph nodes. No other lymphomatous foci were found in either the distant lymph nodes or viscera. This unusual presentation simulates the imaging appearance of surface lesions of bone, namely benign and malignant tumors, and departs from the typical appearance of primary lymphoma of bone. Therefore, this rare type of lymphoma should be considered in the differential diagnosis of surface bone lesions.

Abstract LB-89: Discovery and characterization of novel MTAP splice variants resulting in a hereditary form of osteosarcoma and demonstration of their dysregulation in sporadic forms of this cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Hereditary cancer syndromes represent a powerful and tractable biologic system for identifying cancer-causing genes. Though the syndromes themselves may be rare, their study can provide insights into the basis of the more common sporadic forms of the cancer. Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal dominant bone dysplasia / bone cancer syndrome. This hereditary cancer syndrome is characterized by bone infarctions, cortical growth abnormalities, and pathologic fractures. Most notably, 35% of affected individuals develop bone MFH, a sarcoma that in its sporadic form accounts for 6% of all bone cancers and is believed to be etiologically related to osteosarcoma. Indeed, one of our affected family members developed histologically-proven osteosarcoma, thus further supporting a genetic link between these tumor types. Using a linkage based approach, we previously mapped the DMS-MFH tumor suppressor gene locus to chromosome 9p21-22 (1) and then through LOH analysis demonstrated that hereditary and sporadic forms of MFH most likely share a single underlying genetic etiology (2). We now demonstrate that DMS-MFH results from mutations in the most proximal of three previously unrecognized terminal exons of the methylthioadenosine phosphorylase (MTAP) gene. MTAP is a ubiquitously expressed homotrimeric-subunit enzyme critical to polyamine metabolism and adenine/methionine salvage pathways and was believed to be encoded as a single transcript from the eight previously described exons. Intriguingly, two of the novel MTAP exons arose from early and independent retroviral integration events in primate genomes at least 40 MYR ago and since their genomic integration have gained a functional role. Six distinct retroviral-sequence containing MTAP isoforms, each of which can physically interact with archetype MTAP (i.e., exons 1-8), are identified. The disease-causing / cancer-associated mutations occur within one of these retroviral-derived exons. The mutations result in exon skipping and dysregulated alternative splicing of all MTAP isoforms. Based on these findings in a hereditary form of bone sarcoma, we then analyzed the expression of these MTAP isoforms in a sample set (n=16) of sporadic osteosarcoma samples. All tumor samples expressed similar levels of the archetype MTAP RNA sequence but the expression pattern of the splice variants varied markedly between nearly all the samples. The majority of samples did not express SV1 (n=11/16) and nearly half did not express SV6 (n=9/16). Taken together, these results identify the first gene involved in the development of bone MFH / osteosarcoma and have potential implications for the treatment of this human cancer. References: 1. Am J Hum Genet. 64:801-7; 1999. 2. Genes Chromosomes Cancer. 27:191-5; 2000. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-89. doi:1538-7445.AM2012-LB-89