John D. Reith

Extragastrointestinal (Soft Tissue) Stromal Tumors: An Analysis of 48 Cases with Emphasis on Histologic Predictors of Outcome

The clinicopathologic features of 48 tumors that were histologically similar to gastrointestinal stromal tumors but occurred in the soft tissues of the abdomen were analyzed to determine their overall similarity to their gastrointestinal counterpart, their biologic behavior, and the parameters that predict risk for adverse outcome. Classic leiomyomas and leiomyosarcomas were specifically excluded. The tumors occurred in 32 women and 16 men, who ranged in age from 31 to 82 years (mean, 58 years). Forty tumors arose from the soft tissue of the abdominal cavity, and the remainder arose from the retroperitoneum. They ranged in size from 2.1 to 32.0 cm and varied from tumors composed purely of rounded epithelioid cells to those composed of short fusiform cells set in a fine fibrillary collagenous background with some cases showing a mixed pattern. Tumors displayed variable amounts of stromal hyalinization, myxoid change, and cyst formation. The tumors expressed CD117 (c-kit receptor) (100%), CD34 (50%), neuron-specific enolase (44%), smooth muscle actin (26%), desmin (4%), and S-100 protein (4%). Tumors were evaluated with respect to several parameters: size (<10 cm or >10 cm), cellularity (low or high), mitoses (0 to 2 per 50 high-power fields, >2 per 50 high-power fields), nuclear atypia (1 to 3+), cell type (epithelioid, spindled, or mixed), and necrosis (absent or present). These parameters were then evaluated in univariate and multivariate analysis with respect to adverse or nonadverse outcome, the former defined as metastasis or death from tumor. Follow-up information was obtained for 31 patients (range, 4 to 84 months; median, 24 months). One patient presented with an adverse event and, therefore, was excluded from subsequent analysis. Twelve patients (39%) developed metastases or died of tumor. In univariate analyses, cellularity, mitotic activity (>2 per 50 high-power fields), and necrosis were associated with statistically significant increases in the risk for adverse outcome. Despite the relatively small sample size, in a multivariable analysis mitotic activity (relative risk, 7.46; P =.09) and necrosis (relative risk, 3.75; P =.07) displayed trends toward independent predictive value. No association was noted between histologic pattern and outcome. Although only 39% of tumors behaved in a malignant fashion, this figure probably represents a conservative estimate because long-term follow-up (>5 years) was available for only a limited number of patients. Stratification of patients who have extragastrointestinal stromal tumor into those with 0 to 1 adverse histologic factors versus those with 2 to 3 offers the advantage of separating patients into two groups that have a markedly different risk for adverse outcome in the short term (0.02 events versus 0.54 events per person-year; P<.001, respectively). Extragastrointestinal (soft tissue) stromal tumors are histologically and immunophenotypically similar to their gastrointestinal counterpart but have an aggressive course more akin to small intestinal than gastric stromal tumors.

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive “grungy” calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

Sarcomas arising in dermatofibrosarcoma protuberans: a reappraisal of biologic behavior in eighteen cases treated by wide local excision with extended clinical follow up.

There is a prevailing view that sarcomas arising in dermatofibrosarcoma protuberans (DFSP) have a higher risk of metastasis than ordinary DFSP, but these data are based on cases with variable and often suboptimal treatment. There has not been a large study of sarcomas arising in DFSP in which all cases were treated by wide local excision, thereby arguably altering outcome. Clinicopathologic features of 18 cases of sarcomas arising in DFSP treated by wide local excision and having follow up of at least 5 years were analyzed. An estimate of the proportion of sarcoma and DFSP was made. The number of mitotic figures and degree of CD34 immunoreactivity were assessed in each case. The cohort included 13 females and 5 males (age, 23-87 yrs; median, 47 yrs). The tumors involved the trunk (7), scalp (4), extremities (4), and inguinal region (3), and ranged from 1.5 to 7 cm (median, 4 cm). Sarcoma occurred de novo in 15 cases and in a recurrence in three. Sarcomas resembled fibrosarcoma (17) or malignant fibrous histiocytoma (1) and occupied between 20% and 80% of the tumor (median, 60%). Mitotic activity ranged from 2 to 16 per 10 high-power field (HPF; median 7 per 10 HPF) in the sarcomatous component and 0 to 3 per 10 HPF (median, 1 per 10 HPF) in the DFSP component. All tumors expressed CD34 in the DFSP component but only nine (50%) in the sarcomatous component. All patients were treated by wide local excision with negative margins; three additionally received radiation. Four patients (22%) developed recurrences, but none developed metastasis during the follow-up period of 62 months to 17 years (median, 81.5 mos). In contrast to earlier studies, we demonstrate that patients with sarcomas arising in DFSP do not have an increased risk of distant metastasis within a 5-year follow-up period, provided they are treated by wide local excision with negative margins. This probably reflects the fact that wide local excision results in eradication of local tumor, thereby eliminating the source for subsequent dissemination. However, we cannot completely exclude the possibility that tumors in which clear margins are achieved represent a less aggressive subset, as has been suggested for high-grade extremity sarcomas. Previous studies showing increased metastasis for sarcomas arising in DFSP should be re-evaluated to determine if, with treatment stratification, metastatic rate varies.

Malignant peripheral nerve sheath tumor: Molecular pathogenesis and current management considerations

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are rare tumors that often occur in patients with neurofibromatosis 1. Surgical resection represents the mainstay of treatment. Radiation and chemotherapy have a role in selected patients with MPNST. Accurate pathologic diagnosis remains a challenge in many cases of MPNST. There are many recent advances in the understanding of the molecular pathogenesis of MPNST which represent the best opportunities to develop new strategies for management of patients with MPNST. J. Surg. Oncol. 2008;97:340–349.

Giant cell tumor of the pelvis and sacrum: 17 cases and analysis of the literature.

The optimal treatment of giant cell tumors of the pelvis and sacrum is controversial. Our current patient series was combined with cases identified in a review of the literature published in the past 50 years, yielding a combined group of 239 lesions for study. Recurrence rates were 49% for patients who had radiation therapy alone, 47% for patients who had surgery with intralesional margins, 46% for patients who had surgery with intralesional margins and radiation therapy, and 0% for patients who had surgery with wide margins. Six percent of patients had benign lung metastases develop, 2% of patients had secondary malignancies, 2% of patients died in the perioperative period, and less than 1% of patients had multicentricity. Radiation-induced sarcoma developed in 11% of patients who received radiation for primary or recurrent lesions. Larger doses of radiation therapy did not decrease the rate of local recurrence. Recurrence after surgery and radiation was not lower than after either treatment alone. Local recurrence was more likely in the patients with sacral tumors (48%) than in the patients with pelvic tumors (34%). Disease status was worse in the patients with sacral lesions (23% died of disease) than in the patients with pelvic lesions (6% died of disease).

Angiosarcoma after breast-conserving therapy: experience with hyperfractionated radiotherapy

PURPOSE To report our promising results of hyperfractionated radiotherapy (RT) in conjunction with surgery for angiosarcoma occurring after breast-conserving therapy for early-stage breast cancer. METHODS AND MATERIALS Since 1997, 3 cases of angiosarcoma after breast-conserving therapy have been managed at the University of Florida. The histologic specimens in each case were reviewed and graded by one of us (J.D.R.). RESULTS Explosive growth of discolored skin lesions coincident with histologic evidence of angiosarcoma characterized all 3 cases but was preceded by a fairly indolent period (almost 2 years) of atypical vascular hyperplasia in 2 patients. All 3 patients were treated initially with radical surgery for the angiosarcoma, but extensive recurrences were noted within 1 to 2 months of surgery. Because of the extremely rapid growth noted before and after surgery, hyperfractionated RT was used. Two of the patients underwent planned resection after RT, and neither specimen demonstrated any evidence of high-grade angiosarcoma. All 3 patients were alive without any recurrent disease 22, 38, and 39 months after treatment. CONCLUSIONS Hyperfractionated irradiation appears to be effective treatment for rapidly proliferating angiosarcoma. For previously untreated angiosarcoma, we now recommend hyperfractionated RT followed by surgery to enhance disease control and remove as much reirradiated tissue as possible.

Paraarticular osteochondroma of the knee : report of 2 cases and review of the literature

Paraarticular osteochondromas are unusual osteocartilaginous tumors that arise in the soft tissue adjacent to a joint. Their pathogenesis and classification are controversial, and worrisome histologic features make the distinction from chondrosarcoma difficult on morphologic grounds alone. Two cases of paraarticular osteochondroma of the knee arising in patients 66 and 75 years of age are reported in this study. Although the exact biologic nature of these tumors is not well characterized, limited data suggest that they will behave in benign fashion, similar to soft tissue chondromas. Paraarticular osteochondromas should be recognized to avoid unnecessarily aggressive surgical management.

Pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder that affects the synovium in young and middle-aged adults. Although most believe that it is an inflammatory process, some believe that it is a benign neoplasm. The optimal treatment is surgery. The local recurrence rate after marginal excision for localized PVNS is low. In contrast, the local recurrence rate after open synovectomy for diffuse PVNS is relatively high. The intra-articular instillation of radioactive isotopes or external beam radiotherapy (approximately 35 Gy in 14–15 fractions over 3 weeks) may significantly improve the likelihood of local control and long-term function in patients with incompletely resected diffuse PVNS. The probability of complications after moderate-dose radiotherapy (RT) is low.

The significance of a marginal excision after preoperative radiation therapy for soft tissue sarcoma of the extremity

Marginal excision of soft tissue sarcoma (STS), defined as resection through the tumor pseudocapsule or surrounding reactive tissue, increases the likelihood of local recurrence and necessitates re‐excision or postoperative radiation. However, its impact after preoperative radiation therapy (RT) remains unclear. This study therefore investigated the significance of marginal margins in patients treated with preoperative RT for extremity STS, reporting long‐term local control and limb preservation endpoints.

Acral myxoinflammatory fibroblastic sarcomas: are they all low-grade neoplasms?

Acral myxoinflammatory fibroblastic sarcoma (AMIFS) is a low‐grade sarcoma that presents mostly in distal extremities of middle‐aged patients. The clinicopathologic features, immunohistochemical profile and follow‐up data of five cases (three men and two women; age 39–65 years) are presented. The tumors presented as a slow‐growing, poorly circumscribed, subcutaneous masses in the hands (three), foot (one) and calf (one), with dermal involvement in two cases. They had myxoid and hyaline stroma with dense acute and chronic inflammation. Spindle cells, large bizarre ganglion‐like cells and multivacuolated cells were seen. Variable reactivity in lesional cells were noted for vimentin, Alpha‐1‐antitrypsin (A1AT), factor XIIIa, CD68, CD95, CD117, Alpha‐1‐antichymotrypsin (A1ACT), CD34, AE1/3, S‐100 protein, EBER, CD63 and CD15. MIB‐1 showed 5–30% nuclear labeling. They were negative for cytokeratin AE1/3, smooth muscle actin, CD30, ALK‐1, EMA, desmin, CMV, HMB‐45 and Melan‐A. Follow up ranged from 2 weeks to 95 months (mean 54). One patient was lost to follow up; three underwent excision and one patient had below the knee amputation. Two patients developed metastases (one died of disease), and two patients are alive without evidence of disease. AMIFS are rare tumors that may involve joints and tendons leading to clinical diagnosis of ganglion cyst or tenosynovitis.