David R. Lucas

Phase II Study of Neoadjuvant Chemotherapy and Radiation Therapy in the Management of High-Risk, High-Grade, Soft Tissue Sarcomas of the Extremities and Body Wall: Radiation Therapy Oncology Group Trial 9514

PURPOSE On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting. PATIENTS AND METHODS Eligibility included a high-grade soft tissue sarcoma > or = 8 cm in diameter of the extremities and body wall. Patients received three cycles of neoadjuvant chemotherapy (CT; modified mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]), interdigitated preoperative radiation therapy (RT; 44 Gy administered in split courses), and three cycles of postoperative CT (modified MAID). RESULTS Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant-disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively. CONCLUSION This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.

Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma

As a result of overlapping morphologic and immunohistochemical features, it can be difficult to distinguish synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma/primitive neuroectodermal tumor in core biopsies. To analyze and compare immunohistochemical profiles, we stained tissue microarrays of 23 synovial sarcomas, 23 malignant peripheral nerve sheath tumors, and 27 Ewing sarcomas with 22 antibodies potentially useful in the differential diagnosis, and analyzed the data with cluster analysis. Stain intensity was scored as none, weak, or strong. For CD99, tumors with membranous accentuation were independently categorized. Cluster analysis sorted five groups, with like tumors clustering together. Synovial sarcoma clustered into two groups: one cytokeratin and EMA positive (n=11), the other mostly cytokeratin negative, EMA positive, bcl-2 positive and mostly CD56 positive (n=9). Malignant peripheral nerve sheath tumor clustered into two groups: one S100 positive, with nestin and NGFR positivity in most (n=10), the other mostly S100 negative, and variably but mostly weakly positive for nestin and NGFR (n=11). Ewing sarcomas clustered into a single group driven by membranous CD99 staining. Thirteen cases failed to cluster (outliers), while three Ewing sarcomas clustered into groups of other tumor types. Paired antibodies for each tumor type determined by visual assessment of cluster analysis data and statistical calculations of specificity, sensitivity, and predictive values showed that EMA/CK7 for synovial sarcoma, nestin/S100 for malignant peripheral nerve sheath tumor, and membranous CD99/Fli-1 for Ewing sarcoma yielded high specificity and positive predictive values. Cluster analysis also highlighted aberrant staining reactions and diagnostic pitfalls in these tumors. Hierarchical cluster analysis is an effective method for analyzing high-volume immunohistochemical data.

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.

Undifferentiated Small Round Cell Sarcoma With t(4;19)(q35;q13.1) CIC-DUX4 Fusion A Novel Highly Aggressive Soft Tissue Tumor With Distinctive Histopathology

A subset of small round cell sarcomas remains difficult to classify. Among these, a rare tumor harboring a t(4;19)(q35;q13.1) with CIC-DUX4 fusion has been described. The aim of this study is to better understand its clinicopathologic features. Four cases of CIC-DUX4 sarcoma, all arising in adults (3 women, 1 man, aged 20 to 43 y), were identified using conventional cytogenetic, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methods. All 4 tumors demonstrated CIC-DUX4 fusion transcript by both RT-PCR and FISH and CIC rearrangement by FISH. Cytogenetic results from 2 tumors showed t(4;19)(q35;q13.1) occurring as part of a simple karyotype in 1 tumor and as part of a complex karyotype in the other, the latter from a postchemotherapy specimen. Both tumors harbored trisomy 8 and lacked any other known sarcoma-associated translocation. No EWS or SYT rearrangements were detected by RT-PCR or FISH. The tumors had small round cell morphology with a distinctive constellation of histologic features including extensive geographic necrosis, mild nuclear pleomorphism with coarse chromatin and prominent nucleoli, clear cell areas, and focal myxoid matrix. Only focal staining for CD99 was present in each tumor. Two had very focal cytokeratin staining. All tumors were negative for desmin, myogenin, TLE-1, and S100 protein, whereas nuclear INI-1 staining was retained. The tumors were highly aggressive, and all patients died of disseminated disease within 16.8 months. CIC-DUX4 sarcoma represents a novel translocation-associated sarcoma with distinctive histopathologic features and rapid disease progression.

Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514.

The use of neoadjuvant and adjuvant chemotherapy in soft tissue sarcomas is controversial. This is a report of long‐term (≥5 years) follow‐up in patients with high‐grade, high‐risk soft tissue sarcomas treated with neoadjuvant chemotherapy, preoperative radiotherapy (RT), and adjuvant chemotherapy.

Sino-orbital osteoma: a clinicopathologic study of 45 surgically treated cases with emphasis on tumors with osteoblastoma-like features.

CONTEXT Osteomas are limited almost exclusively to craniofacial and jaw bones. Histologically, they can be divided into ivory, mature, or mixed types. Osteomas may have osteoblastoma-like areas and distinguishing it from true osteoblastoma can be challenging. Some believe osteomas with osteoblastoma-like features behave more aggressively. OBJECTIVE To perform a clinicopathologic comparison of sino-orbital osteomas both with and without osteoblastoma-like features. DESIGN We studied 45 surgically excised sino-orbital osteomas. Tumors were categorized as ivory, mature, or mixed type and presence of osteoblastoma-like areas and Paget-like bone were noted. Clinical features of those with and without osteoblastoma-like areas were compared. RESULTS Men outnumbered women (3:2); median age was 37 years. Frontal sinus was the most common location (62%) followed by ethmoid and maxillary sinuses. Twelve tumors (27%) involved the orbit, 2 primarily and 10 secondarily. All cases were symptomatic with headache, sinusitis, visual changes, pain, and proptosis being most common. Seventeen tumors (38%) had osteoblastoma-like areas. Extension into an adjacent sinus/anatomic compartment was more common in osteoblastoma-like tumors (47% versus 29%), including more frequent orbital involvement (41% versus 13%). Visual changes were more frequent in the osteoblastoma-like group. Distribution of histologic subtypes and Paget-like bone were similar between the 2 groups. Osteomas with osteoblastoma-like features were more often incompletely excised (25% versus 14%). However, clinical recurrence was less common (8% versus 27%). CONCLUSIONS Osteoblastoma-like features are common in sino-orbital osteomas, but it does not correlate with more adverse clinical features or worse outcome. Osteoblastoma-like areas appear to represent active remodeling within an osteoma rather than defining a distinct clinicopathologic entity. Distinguishing it from osteoblastoma may require careful histologic evaluation and radiographic correlation.

Extensive Survey of STAT6 Expression in a Large Series of Mesenchymal Tumors

OBJECTIVES Expression of strong nuclear STAT6 is thought to be a specific marker for solitary fibrous tumors (SFTs). Little is known about subtle expression patterns in other mesenchymal lesions. METHODS We performed immunohistochemical studies against the C-terminus of STAT6 in tissue microarrays and whole sections, comprising 2366 mesenchymal lesions. RESULTS Strong nuclear STAT6 was expressed in 285 of 2,021 tumors, including 206 of 240 SFTs, 49 of 408 well-differentiated/dedifferentiated liposarcomas, eight of 65 unclassified sarcomas, and 14 of 184 desmoid tumors, among others. Expression in SFTs was predominately limited to the nucleus. Other positive tumors typically expressed both nuclear and cytoplasmic STAT6. Complete absence of STAT6 was most common in pleomorphic liposarcoma and alveolar soft part sarcoma (60% and 72% cases negative, respectively). CONCLUSIONS Strong nuclear STAT6 is largely specific for SFTs. Physiologic low-level cytoplasmic/nuclear expression is common in mesenchymal neoplasia and is of uncertain significance.

Significant Reduction of Late Toxicities in Patients With Extremity Sarcoma Treated With Image-Guided Radiation Therapy to a Reduced Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial

PURPOSE We performed a multi-institutional prospective phase II trial to assess late toxicities in patients with extremity soft tissue sarcoma (STS) treated with preoperative image-guided radiation therapy (IGRT) to a reduced target volume. PATIENTS AND METHODS Patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Daily pretreatment images were coregistered with digitally reconstructed radiographs so that the patient position could be adjusted before each treatment. All patients received IGRT to reduced tumor volumes according to strict protocol guidelines. Late toxicities were assessed at 2 years. RESULTS In all, 98 patients were accrued (cohort A, 12; cohort B, 86). Cohort A was closed prematurely because of poor accrual and is not reported. Seventy-nine eligible patients from cohort B form the basis of this report. At a median follow-up of 3.6 years, five patients did not have surgery because of disease progression. There were five local treatment failures, all of which were in field. Of the 57 patients assessed for late toxicities at 2 years, 10.5% experienced at least one grade ≥ 2 toxicity as compared with 37% of patients in the National Cancer Institute of Canada SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) trial receiving preoperative radiation therapy without IGRT (P < .001). CONCLUSION The significant reduction of late toxicities in patients with extremity STS who were treated with preoperative IGRT and absence of marginal-field recurrences suggest that the target volumes used in the Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) study are appropriate for preoperative IGRT for extremity STS.

ROLE OF RADIOTHERAPY IN THE MANAGEMENT OF DESMOID TUMORS

PURPOSE To identify high-risk patients with desmoid tumors who could benefit from postoperative radiotherapy (RT) and to determine the efficacy of postoperative and definitive RT. MATERIALS AND METHODS Retrospective analysis of clinical data for all patients with desmoid tumors who underwent definitive local therapy at the University of Michigan from 1984 through 2008. Estimates for local control were calculated using the product-limit method of Kaplan and Meier, and associations with patient, tumor, and RT characteristics were explored using Cox proportional hazard regression. RESULTS Treatment for 95 patients who qualified for the study included surgery, RT, or both in 54, 13, and 28 cases, respectively. With a median follow-up of 38 months, the actuarial 3-year local control (95% confidence interval [CI]) was not significantly different (p = 0.3) among the three treatment groups: 84.6% (70.2-92.4), 92.3% (56.6-98.9), and 69.0% (43.1-84.9), respectively. Tumor site in the head/neck (p = 0.03) and history of previous surgical therapy (p = 0.01) were associated with increased recurrence risk (HR = 2.8, 95% CI 1.1-7.4, and HR = 3.2, 95% CI = 1.3-7.8), whereas gender, age, use of RT, and positive margins were not (p > 0.2). CONCLUSIONS Our findings suggest equivalent local control rates after surgery, RT, or a combination of both. Although history of previous surgical therapy or site of origin in the head/neck region were found to be associated with increased risk of recurrence after local therapy, there was no clear association between surgical margin status and local control.

Angiosarcoma, Radiation-Associated Angiosarcoma, and Atypical Vascular Lesion

Angiosarcoma, one of the least common sarcomas, has become increasingly important because of its association with radiation therapy, especially for breast cancer. Most are sporadic, presenting as cutaneous tumors in the scalp/face of elderly patients. However, angiosarcoma has a wide anatomic distribution including soft tissue, visceral organ, and osseous locations. Predisposing conditions include environmental exposures to chemical or radioactive sources. Radiation-associated angiosarcoma typically presents as a cutaneous tumor several years posttherapy. The latency for radiation-associated mammary angiosarcoma is relatively short, sometimes less than 3 years. Atypical vascular lesion refers to a small, usually lymphatic-type vascular proliferation in radiated skin. Although most atypical vascular lesions pursue a benign course, they recur and very rarely progress to angiosarcoma. Distinguishing this lesion from well-differentiated angiosarcoma in a biopsy can be challenging, especially because areas indistinguishable from atypical vascular lesion are found adjacent to angiosarcoma. Recently, vascular-type atypical vascular lesion, which resembles hemangioma, has been described, thus expanding the definition of this entity.