Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330.

Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

Differential expression of HER-2/NEU receptor of invasive mammary carcinoma between Caucasian and African American patients in the Detroit metropolitan area. Correlation with overall survival and other prognostic factors.

GOALS: HER-2/neu overexpression in invasive mammary carcinoma is associated with more aggressive biologic behavior. Breast cancer in African American (AA) women has been associated with a shorter survival rate than that seen in Caucasians (C). This study evaluated the frequency of HER-2/neu overexpression in C compared to AA patients and the association of HER-2/neu expression with overall survival and other prognostic factors. METHODS: A retrospective review of the SEER data of Karmanos Cancer Institute for patients with invasive mammary carcinoma was conducted between 1998 and 2001. Pathology reports and pathology slides were obtained for those patients with missing data. Available data and material on 608 patients were found. The median follow-up interval was 35 months with a range of 1-91 months. 46.7% of the study population was C while 53.3% was AA. The differential of HER-2/neu expression in C and AA was evaluated. The association of HER-2/neu expression and other prognostic factors with overall survival was carried out by univariate and multivariable analyses using Cox's proportional hazards regression model. PRINCIPLE RESULTS: No statistically significant difference was found in HER-2/neu expression between C and AA patients. Overexpression of HER-2/neu did not correlate with decreased overall survival in this analysis. MAJOR CONCLUSIONS: Breast cancer HER-2/neu expression in AA patients is not statistically different from that of Caucasians. HER-2/neu expression is not associated with overall survival. Among the other prognostic factors analyzed, ER status and histologic grade were not statistically significant.

Sarcomatoid mesothelioma and its histological mimics: a comparative immunohistochemical study.

AIMS: Differentiating sarcomatoid mesothelioma from other pleural-based spindle cell tumours by light microscopy can be challenging, especially in a biopsy. The role of immunohistochemistry in this differential diagnosis is not as well defined as it is for distinguishing epithelioid mesothelioma from adenocarcinoma. In this study, we investigate the utility of diagnostic immunohistochemistry for distinguishing sarcomatoid mesothelioma from its histological mimics, high-grade sarcoma and pulmonary sarcomatoid carcinoma. METHODS: We stained 20 mesotheliomas with sarcomatoid components (10 biphasic and 10 sarcomatoid mesotheliomas) for pan-cytokeratin, cytokeratin 5/6, calretinin, WT-1, thrombomodulin, and smooth muscle actin. Intensity and distribution of staining were assessed using a semiquantitative scale. Only tumours with unequivocal staining were considered positive for tabulation. We compared the immunophenotypic profiles of these tumours with 24 high-grade sarcomas, 10 pulmonary sarcomatoid carcinomas, and 16 epithelioid mesotheliomas. The sarcomatoid carcinomas were also stained for thyroid transcription factor-1 (TTF-1). RESULTS: Pan-cytokeratin stained 70% of sarcomatoid mesotheliomas, 17% of sarcomas, 90% of sarcomatoid carcinomas, and 100% of epithelioid mesotheliomas. Cytokeratin 5/6 and WT-1 stained most epithelioid mesotheliomas, but rarely stained sarcomas, sarcomatoid carcinomas, or the sarcomatoid components of mesothelioma. Calretinin and thrombomodulin each stained 70% of sarcomatoid mesotheliomas. However, calretinin was also positive in 17% of sarcomas and in 60% of sarcomatoid carcinomas, while thrombomodulin was positive in 38% of sarcomas and in 40% of sarcomatoid carcinomas. Smooth muscle actin was expressed in 60% of sarcomatoid mesotheliomas and in 58% of sarcomas, but in only 10% of sarcomatoid carcinomas. All 10 sarcomatoid carcinomas were negative for TTF-1. CONCLUSIONS: Mesothelioma shows decreased expression of epithelial and mesothelial epitopes in its sarcomatoid components. A wide immunophenotypic overlap exists among sarcomatoid mesotheliomas, sarcoma, and sarcomatoid carcinomas. Cytokeratin and calretinin have the most value in differentiating sarcomatoid mesothelioma from sarcoma. However, because sarcomatoid mesothelioma can occasionally be cytokeratin-negative, the distinction between it and sarcoma may become arbitrary. With the exception of smooth muscle actin, all the markers studied showed similar distributions in sarcomatoid mesothelioma and sarcomatoid carcinoma, including frequent calretinin and thrombomodulin expression in both tumours. Thus, immunohistochemistry plays a more limited role in the differential diagnosis of sarcomatoid tumours compared with epithelioid tumours. For sarcomatoid tumours involving the pleural lining, clinicopathological data, especially information about the gross appearance of the tumour (i.e. localized versus diffuse pleural-based mass), should be noted and carefully correlated with microscopic and immunohistochemical findings.

Fine-needle aspiration biopsy of vertebral and intervertebral disc lesions: specimen adequacy, diagnostic utility, and pitfalls.

BACKGROUND AND OBJECTIVES: Fine-needle aspiration biopsy (FNAB) is used extensively in the clinical workup of radiologically detected bony lesions. The aims of this study were to evaluate the diagnostic utility of FNAB of such radiologically detected vertebral and intervertebral disc lesions in patients with and without a known primary malignancy, to establish criteria for specimen adequacy, and to evaluate the diagnostic pitfalls. DESIGN: The cytologic material obtained by FNAB performed under computed tomographic guidance of 78 cases comprising 66 vertebral and 12 intervertebral disc lesions was reviewed and analyzed. The initial cytologic diagnosis was compared with the diagnosis after review in all 78 cases. RESULTS: Thirty-five cases (45%) were positive for malignancy, 1 case (1.3%) was suspicious for malignancy, 9 (11.5%) consisted of normal cellular elements with no evidence of malignancy, 21 (27%) were unsatisfactory/inadequate for diagnosis, and 12 (15.2%) were benign nonneoplastic lesions. Nonneoplastic lesions diagnosed included fracture callus, discitis/osteomyelitis, degenerative disc disease, and Paget disease. In 11 cases, FNAB gave the initial diagnosis of malignancy (8 occult carcinomas and 3 plasmacytomas). In 23 out of 36 cases with a clinical history of a known primary tumor, FNAB established the diagnosis of metastases, and in 1 case, a second primary was detected. CONCLUSIONS: Fine-needle aspiration biopsy of radiologically suspected vertebral and intervertebral disc lesions in patients with a history of a known malignancy is useful to confirm the presence of metastases. In cases without any history of malignancy, FNAB can provide additional clues to aid in the subsequent workup and treatment of cases diagnosed with an unsuspected malignancy and other nonneoplastic lesions. Through assessment of the specimen adequacy, correct interpretation of the cytologic material available, and correlating with the clinical and radiologic findings, a definitive diagnosis can be made in most cases.

Ewing sarcoma vs lymphoblastic lymphoma. A comparative immunohistochemical study.

To develop a practical immunohistochemistry panel for distinguishing lymphoblastic lymphoma from Ewing sarcoma (ES), we evaluated 17 ES and 27 lymphoblastic lymphoma and leukemia cases with antibodies to CD99, terminal deoxynucleotidyl transferase (TdT), leukocyte common antigen (LCA), CD43, CD79a, CD20, CD3, vimentin, and neuron-specific enolase (NSE). Three cases were bone lymphomas, 2 initially misdiagnosed as ES. All cases were CD99+. All lymphomas and leukemias were TdT+ compared to none of the ESs. None of the ESs expressed other lymphocytic markers, which were inconsistently expressed in the lymphomas and leukemias: CD43, 33%; LCA, 30%; CD79a, 19%; CD3, 19%; and CD20, 7%. Of the ESs, 88% were vimentin positive compared with 23% of lymphomas and leukemias. Vimentin was stronger and more diffuse in ES. NSE did not reliably stain any cases. When faced with the differential diagnosis of ES vs lymphoblastic lymphoma, an immunohistochemical panel that includes antibodies to CD99 and TdT is useful. Both epitopes are well preserved in fixed and decalcified tissue. A panel composed of antibodies to CD99 and TdT, in conjunction with other lymphocytic markers and vimentin, is highly sensitive and specific.

Arthroplasty-associated malignant fibrous histiocytoma: two case reports.

AIMS: Sarcoma localized to the site of an arthroplasty procedure is a rare occurrence, and detailed histological depictions and descriptions are limited. We report the clinicopathological findings in two cases of arthroplasty-associated malignant fibrous histiocytoma (MFH) and review the literature. METHODS AND RESULTS: The patients were an elderly man and woman. Medical histories, radiographs and slides were reviewed. Immunohistochemistry, electron microscopy, cytogenetics, and electron dispersion spectroscopy were performed in one case. Both were destructive femoral bone tumours that appeared 2 and 8 years post-total hip arthroplasty, and pursued aggressive clinical courses. The histology was similar in both tumours, consisting of high-grade, pleomorphic sarcoma with numerous osteoclastic giant cells, prominent phagocytic activity, and entrapped particles of bone cement. Literature review disclosed 14 previous reports of arthroplasty-associated MFH, representing the most common phenotype. A number of materials and factors related to arthroplasty procedure, such as metal corrosion, wear debris, osteonecrosis, and chronic inflammation, have been implicated as causative agents. CONCLUSIONS: Arthroplasty-associated MFH is a rare and aggressive tumour. Although the aetiology remains unclear, the small number of arthroplasty-associated sarcomas compared with the large number of joint replacement operations performed over the past four decades suggests a coincidental as opposed to a causal relation.

Primary alveolar soft part sarcoma of bone.

AIMS: Alveolar soft part sarcoma is a distinct, rare soft tissue tumour occurring primarily within the skeletal muscles or musculofascial planes in young adults. Primary involvement of bone is extremely rare. We report on six patients with alveolar soft part sarcoma occurring primarily in bone. METHODS AND RESULTS: Thorough clinical and radiographic examinations were done to rule out any other primary site. The patients were four women and two men aged 17-35 years (mean, 24.5 years). The primary site of the tumour was the femur in three patients, the ilium in one and the fibula in two. In one of the patients with fibular involvement, the tibia was also involved by direct extension. Of the long bone lesions, three were centred in the metaphysis and one in the diaphysis. Radiographically, all of the lesions demonstrated an osteolytic pattern of bone destruction with ill-defined margins and a wide zone of transition between the lesion and adjacent normal bone. Microscopically, all tumours showed the typical histological pattern of alveolar soft part sarcoma. Diastase-resistant, periodic acid-Schiff-positive crystalline structures were identified within the cytoplasm and confirmed ultrastructurally. Immunohistochemically, a keratin stain was negative in all cases; there was positive staining for MyoD1 in the cytoplasm but not the nuclei. Distant metastasis developed in four patients; one died. CONCLUSION: Alveolar soft part sarcoma arising in bone is extraordinarily rare but should be considered in the differential diagnosis of metastatic hypernephroma in a young patient.

Multidrug resistance phenotype in high grade soft tissue sarcoma: correlation of P-glycoprotein immunohistochemistry with pathologic response to chemotherapy.

BACKGROUND: P-glycoprotein-mediated drug efflux has been implicated as an important mechanism of multidrug resistance (MDR) in cancer. Its role in chemotherapy resistance in soft tissue sarcoma is unclear. METHODS: Tumor specimens prior to and following neoadjuvant chemotherapy from 29 cases of high grade soft tissue sarcoma were analyzed with 2 monoclonal antibodies (C494 and JSB-1) that recognize different epitopes of P-glycoprotein. Staining intensity was graded 0 = negative, 1 = equivocal, 2 = moderate, 3 = strong. Only cases with Grade 2 or 3 staining intensity with both antibodies were considered MDR positive. The resection specimens were evaluated for tumor necrosis postchemotherapy. Pathologic response was graded as good for <15%, moderate for 15-50%, or poor for >50% posttreatment tumor viability. RESULTS: Of the 29 pretreatment specimens, 10 (34%) were MDR positive and 19 (66%) were MDR negative. Pathologic response to treatment was characterized as good in 6, moderate in 7, and poor in 16 patients. Of the MDR positive biopsies, 9 (90%) had poor response, compared with 7 (36%) in the MDR negative biopsy group (P = 0.0078). None of the cases with MDR positive biopsies had a good response, compared with 6 cases in which biopsies were MDR negative (32%) (P = 0.057). Only one MDR negative case became MDR positive posttreatment. CONCLUSIONS: Expression of MDR phenotype is found in approximately one-third of high grade soft tissue sarcomas. These preliminary data show a significant correlation between MDR phenotype and poor pathologic response to chemotherapy, and suggest that MDR induction by chemotherapy in soft tissue sarcoma is an uncommon event.

High-grade extraskeletal myxoid chondrosarcoma: a high-grade epithelioid malignancy.

AIMS: Extraskeletal myxoid chondrosarcoma is typically a low-to-intermediate grade sarcoma that is associated with a prolonged clinical course. High-grade forms are rare and not well characterized. In this series we report the clinicopathological, immunohistochemical and ultrastructural findings in four cases of high-grade extraskeletal myxoid chondrosarcoma. METHODS AND RESULTS: The patients were three men and one woman (ages 34-73 years) with tumours located in the thigh (two cases), paraspinal soft tissue and perineum. Three patients had metastases, one at 12 weeks, one at 10 months, and one at presentation of recurrent tumour. In the latter case the original tumour was low grade and became high grade when it recurred 3.5 years later. All three patients died of disease. One patient was lost to follow-up. The most striking histological feature in all four tumours was the presence of numerous large epithelioid cells. These cells were arranged in cords within myxoid matrix and in sheets devoid of matrix. Two tumours had areas of conventional extraskeletal myxoid chondrosarcoma intermixed with the high-grade areas. One tumour showed transition to high-grade spindle cell sarcoma. One tumour had cells with rhabdoid features. Immunohistochemically, two tumours focally expressed S100 protein, and one focally expressed EMA. All were negative with cytokeratin, desmin, smooth muscle actin, HMB45, CD31 and CD34. Ultrastructural features in three cases were compatible with chondrosarcoma; one tumour had aggregates of microtubules within rough endoplasmic reticulum, a characteristic feature of this tumour. CONCLUSIONS: High-grade extraskeletal myxoid chondrosaroma is a rare and aggressive soft tissue sarcoma, and should be included in the differential diagnosis of other epithelioid malignancies.

Spindle cell tumors associated with mycobacteria in lymph nodes of HIV-positive patients: 'Kaposi sarcoma with mycobacteria' and 'mycobacterial pseudotumor'.

Patients infected with HIV often have unusual manifestations of common infections and neoplasms. One such example is "mycobacterial pseudotumor," an exuberant spindle cell lesion induced in lymph nodes by mycobacteria. Kaposi sarcoma also produces a spindle cell proliferation in lymph nodes of HIV-positive patients. These two entities must be differentiated from one another because of differences in treatment and prognosis. We report here, however, three cases of intranodal Kaposi sarcoma with simultaneous mycobacterial infection, the occurrence of which has not been clearly documented. For comparison, we also studied three cases of mycobacterial pseudotumor, of which 14 cases have been described to date. There was considerable histologic overlap between these two lesions. Acid-fast bacilli were present in all cases, predominantly in the more epithelioid histiocytes in the cases of Kaposi sarcoma, and in spindle and epithelioid cells in the cases of mycobacterial pseudotumor. The morphologic features that favored Kaposi sarcoma over mycobacterial pseudotumor were the prominent fascicular arrangement of spindle cells and slitlike spaces, the lack of granular, acidophilic cytoplasm, and the presence of mitoses. Immunohistochemistry was a reliable adjunct study in the differential diagnosis, as the spindle cells in mycobacterial pseudotumor were positive for S-100 protein and CD68 whereas those of Kaposi sarcoma were CD31- and CD34-positive but negative for S-100 protein and CD68. Awareness that Kaposi sarcoma may coexist with mycobacterial infection in the same biopsy specimen is important because these lesions may be misdiagnosed as mycobacterial pseudotumor. The clinical impact of distinguishing between Kaposi sarcoma with mycobacteria and mycobacterial pseudotumor is significant because the presence of Kaposi sarcoma alters treatment and prognosis.

Pathology of the posterior tibial tendon in posterior tibial tendon insufficiency.

Gross and histologic examinations of 15 normal cadaver and 15 surgical posterior tibial tendons from patients with posterior tibial tendon insufficiency were performed. All surgical specimens were abnormal with enlargement distal to the medial malleolus and a dull white appearance. At histologic examination, 12 of 15 cadaver tendons displayed normal tendon structure characterized by linear orientation of collagen bundles, normal fibroblast cellularity, low vascular density, and insertional chondroid metaplasia. The surgical specimens displayed a degenerative tendinosis characterized by increased mucin content, fibroblast hypercellularity, chondroid metaplasia, and neovascularization. This resulted in marked disruption of the linear orientation of the collagen bundles.

Gender differences in physiological reactivity to infant cries and smiles in military families.

OBJECTIVE: The primary purpose of this experiment was to examine gender differences in physiological reactivity to infant cries and smiles in military families. METHOD: Twenty males and 29 females viewed and listened to videotapes of a crying infant and a smiling infant while heart rate, skin resistance, and respiration rate were monitored. All participants were active-duty U.S. Air Force personnel or their spouses. RESULTS: Males showed a larger increase in skin conductance than females during the crying infant stimulus. Males also showed an increase in heart rate during the crying infant stimulus, whereas females did not show any increase in heart rate during the crying infant stimulus. No gender differences in physiological reactivity were obtained during the smiling infant stimulus, although both males and females showed a significant increase in heart rate while viewing the smiling infant. CONCLUSIONS: The results are contrasted with previous reports (e.g., Frodi, Lamb, Leavitt, & Donovan, 1978) of no differences between genders in physiological reactivity to a crying infant. Discussion of the results focuses on models of child physical abuse that involve physiological hyperreactivity. It is hypothesized that the greater physiological reactivity of males than females during a crying infant videotape may partially explain why physical abuse of a child by a male frequently results in more serious damage to the child than physical abuse by a female.

Visualizing the perisaccadic shift of spatiotopic coordinates.

A point light source flickering on and off during a horizontal saccade projects a horizontal array onto the retina. The apparent visual direction of the tail end of the perceived (phantom) array reflects the amount of perisaccadic shift of spatiotopic coordinates that has been completed by the end of the saccade. Four men, saccading 8 degrees to the right across a flashing light, judged the horizontal visual direction of the left (tail) end of the phantom array relative to the left end of a standard 8 degrees array that had projected an image onto the retina before the saccade began. On average, the left ends appeared to be aligned when the last flash in the phantom array was imaged on the retina 7.4 degrees to the right of the image of the left end of the standard array. This result implies that the shift of spatiotopic coordinates is virtually complete by the end of the saccade.

The elemental composition of tumors: kerma data for neutrons.

The elemental composition of a variety of tumor samples, including squamous cell lung carcinoma, sarcoma, adenoid cystic carcinoma, melanoma, and rectal carcinoma have been measured by combustion analysis. Hydrogen, carbon, nitrogen, and oxygen content have been determined. Using the elemental neutron kerma data published in ICRU Report #46 the neutron kerma factors for the various tumor samples have been calculated in the energy range 11 eV to 29 MeV. The average neutron kerma values for all tumor samples are approximately 6%-7% lower than those for average soft tissue in the energy range of interest in fast neutron therapy (energies > 1 MeV).

Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation.

Desmoid tumor is a locally aggressive, nonmetastasizing soft tissue tumor. Whether desmoid tumor is a truly neoplastic cellular proliferative process or, alternatively, an unchecked reactive process has been a subject of debate. In order to determine whether desmoid tumor is composed of a clonal cell population as opposed to being a polyclonal reactive process, analysis of patterns of X-chromosome inactivation was performed. Hematoxylin and eosin stained sections of paraffin-embedded, formalin-fixed tissues were microdissected to obtain both lesional and normal control samples, and the genomic DNAs were extracted by proteinase K digestion. Following treatment with methylation sensitive restriction endonuclease (Hha I or Hpa II), the genomic DNAs were amplified by polymerase chain reaction (PCR), using nested primers targeted to a highly polymorphic short tandem repeat (STR) of the human androgen receptor (HUMARA). In eight of 12 cases, PCR amplification of the genomic DNAs was successful, and all eight of the amplified cases were heterozygous in the size of the HUMARA target. The remaining cases could not be studied because of failure to amplify DNA. Following digestion with HhaI or Hpa II, uniform patterns of X-chromosome inactivation were found in all eight desmoid tumors, whereas normal control tissue remained heterozygous. These results confirm a clonal composition of the tumors. The demonstration of clonality in the tumors in all eight informative cases indicates that desmoid tumor is a true neoplastic process, not an unchecked polyclonal reactive process.