Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases.

PURPOSE: This study investigated prognostic factors in nonmetastatic high-grade extremity osteosarcoma and the prognosis following resection of subsequent pulmonary metastases, with emphasis on the effect of chemotherapy-induced tumor necrosis. PATIENTS AND METHODS: We reviewed 111 consecutive patients with high-grade nonmetastatic extremity osteosarcoma treated with preoperative chemotherapy and surgical resection, with additional review of 36 patients who had subsequent pulmonary metastases resected. RESULTS: The overall 5-year survival rate was 53%. In resected primary tumors, tumor-free resection margin (P < .001) and increasing chemotherapy-induced tumor necrosis (> 90% threshold, P < .003) correlated with increased metastasis-free survival. Relative risk factors for metastases were as follows: tumor-containing resection margin (most likely to metastasize); poor response to preoperative chemotherapy and/or lack of postoperative chemotherapy (next worse prognosis); and excellent response to preoperative chemotherapy (> or = 90% necrosis) combined with postoperative chemotherapy (best prognosis). The 5-year survival rate following pulmonary metastasis resection was 23%, whereas a 0% 4-year survival rate followed development of bony metastases (P < .001). The extent of tumor necrosis in resected pulmonary metastases did not affect prognosis. Survival was best in patients with three or fewer pulmonary nodules (P < .048), four or fewer recurrent pulmonary nodules (P < .047), unilateral pulmonary metastases (P < .037), or longer intervals between primary tumor resection and metastases (P < .082). CONCLUSION: Intensive preoperative and postoperative chemotherapy combined with complete resection of both primary and metastatic pulmonary osteosarcomas is justified, with a goal of 100% tumor necrosis and excision. Although current treatment regimens allow effective salvage therapy for a few patients with pulmonary metastases, more effective systemic treatment is needed.

Atypical and malignant variants of ossifying fibromyxoid tumor. Clinicopathologic analysis of six cases.

Ossifying fibromyxoid tumor (OFMT) of soft parts is a recently defined fibro-osseous neoplasm, the biologic behavior of which is generally regarded as benign. We report six variant cases of OFMT with histologic features of malignancy, two of which behaved aggressively. All these tumors arose in the extremities of adults (aged 36-76 years), and five of the six were subcutaneous. Four patients were men. Macroscopically, all the tumors were well circumscribed and somewhat lobulated. Cardinal morphologic features included lobules of round to spindled cells within a fibromyxoid matrix and randomly distributed, often centrally located osteoid within which were plump neoplastic cells. In contrast to typical OFMT, a hypocellular, cytologically benign, lamellar bony shell was observed only focally; cellularity was increased (four cases), and mitotic activity was frequent, exceeding two mitotic figures per 10 high-power fields (three cases). One case associated with metastases was morphologically bland. Immunohistochemically, positivity for S-100 protein was observed in the primary tumors of three cases and in the pulmonary metastasis of a fourth. Desmin was positive in one case. Ultrastructural features in three cases were very similar to usual OFMT. Clinical follow-up revealed local recurrence in two cases; one patient has developed recurrent pulmonary metastases. We believe these findings support the view that some atypical cases of OFMT exhibit morphologic patterns that might predict more aggressive behavior.

Characterization and localization of receptors for epidermal growth factor in ovine skin.

Specific receptor sites for murine epidermal growth factor (EGF) have been characterized and their distribution determined in ovine skin. Binding of 125I-labelled EGF to skin membrane particles was temperature- and time-dependent, with equilibrium being reached within 1 h at 23 degrees C. Analysis of skin biopsies collected from ten castrated Merino sheep demonstrated the presence of a single class of saturable, high-affinity binding sites with a dissociation constant of 64 +/- 4 (S.E.M.) pmol/l and a binding capacity of 33.8 +/- 4.5 fmol/mg protein. Skin particle binding of 125I-labelled EGF was inhibited equipotently by mouse salivary gland EGF, EGF produced by recombinant DNA procedures and urogastrone. The EGF peptides 1-48, 6-53 and 7-53, derived from the native molecule by enzymatic cleavage, were much less potent. The relative binding potency of these molecules was correlated with their ability to induce precocious eyelid opening in mice and to inhibit wool follicle activity. Synthetic fragments representing the major structural domains of the EGF molecule (EGF(29-44), EGF(33-42) and EGF(3-31] were inactive in both the receptor and bioassays. Autoradiography of skin sections incubated with 125I-labelled EGF in vitro or of sections from skin which was perfused with 125I-labelled EGF in vivo demonstrated that EGF receptors were localized in undifferentiated cells of the epidermis and sebaceous glands, the inner and outer root sheath and bulb of wool follicles and in dermal arterioles. Differences in receptor concentration were observed between follicles following in-vivo perfusion of 125I-labelled EGF but not when the in-vitro labelling technique was used. The presence of receptors in these regions is consistent with the morphological changes in sheep skin in response to EGF administration which have been reported previously.

Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? Experience with 140 patients.

We reviewed the clinicopathologic features of 145 consecutive fine-needle aspiration biopsy (FNAB) specimens from 140 patients without a previous diagnosis of sarcoma. Among 138 adequate specimens, 42 bone sarcomas and 80 soft tissue sarcomas were recognized as sarcomas; histologic subtyping was easier in bone than in soft tissue sarcomas and in pediatric than in adult cases. There was no correlation in accuracy of subtyping in low- vs high-grade sarcomas. FNAB was most accurate for subtyping of skeletal osteosarcoma, pediatric small round cell bone/soft tissue sarcomas, synovial sarcoma, skeletal chondrosarcoma, and adult myxoid soft tissue sarcomas. Although almost always recognized as sarcoma, subtyping of adult pleomorphic soft tissue sarcomas generally was not possible but did not influence therapy; all were considered high-grade sarcomas for treatment purposes. There were 4 misinterpretations of subtype in soft tissue sarcomas; none resulted in a change in therapy. Cytogenetic analysis on aspirated material confirmed t(11;22) in 2 Ewing and t(X;18) in 3 synovial sarcomas. No procedure-related complications occurred. Among bone and soft tissue sarcomas, FNAB was sufficient for initiation of definitive therapy in 87% and 83% of patients, respectively. Most FNAB specimens from bone and soft tissue sarcomas are recognized easily as sarcoma, but subtyping seems more accurate in bone sarcomas. Although histologic subtyping of adult soft tissue sarcomas is often impossible, no influence on initial therapy is usually observed. In contrast, subtyping of pediatric sarcomas by FNAB seems highly accurate and is necessary for appropriate therapy.

Fine-needle aspiration biopsy of soft tissue sarcomas. A cytomorphologic analysis with emphasis on histologic subtyping, grading, and therapeutic significance.

Because therapy for sarcoma often incorporates histologic subtype, grade, stage, and anatomic location, establishing a specific histologic subtype often is essential. To evaluate the effectiveness of fine-needle aspiration biopsy (FNAB) in histologic subtyping of soft tissue sarcomas, we retrospectively reviewed 73 consecutive aspirates from 67 patients, none of whom had a previously established sarcoma diagnosis. Sarcoma cases were subgrouped according to predominant cytomorphologic features: pleomorphic cell, 19; small round cell, 18; spindle cell, 18; myxoid, 10; epithelioid/polygonal cell, 7; 1 case of well-differentiated liposarcoma was analyzed separately. Ancillary studies were used for 25 cases. Among adequate specimens, 61 tumors were recognized as sarcoma. A specific and accurate histologic subtype was determined in 34 cases. Ancillary studies were most useful for histologic subtyping of small round cell and spindle cell sarcomas. Myxoid sarcomas were subtyped easily based solely on histomorphologic features. Pleomorphic cell and epithelioid/polygonal cell sarcomas were recognized easily as malignant but difficult to subtype by FNAB. With the exception of small round cell sarcomas, histologic subtyping of a sarcoma usually did not directly influence therapy. With meticulous attention to clinicopathologic features and ancillary techniques, many sarcomas, especially small round cell, spindle cell, and myxoid types, may be subtyped successfully by FNAB, within limitations.

Fine-needle aspiration biopsy of synovial sarcoma. A cytomorphologic analysis of primary, recurrent, and metastatic tumors.

Thirteen fine-needle aspiration specimens from 10 patients with histologically proven synovial sarcoma are described. The aspiration biopsy specimens were obtained from the primary tumor in five cases, locally recurrent tumors in four cases, pulmonary metastases in three cases, and mediastinal metastasis in one case. Patient's ages ranged from 22 years to 65 years; there were four women and six men. All cases had a confirmation biopsy and/or resection specimen that were reviewed. Histologic subtypes included monophasic fibrous (5 cases), monophasic epithelial (1 case), biphasic (3 cases), and poorly differentiated (1 case). The majority of the aspiration biopsy specimens were similar with moderate to marked smear cellularity dominated by cohesive clusters of spindle-shaped cells with ovoid, hyperchromatic nuclei and scanty tapering cytoplasm. Nucleoli were not prominent. Epithelial tumor cells with ovoid to round, mostly regular, centrally to eccentrically located nuclei, surrounded by scant to abundant cytoplasm predominated in one case (monophasic epithelial) and were admixed with spindle cells in a second (classical biphasic). Multi-nucleated tumor giant cells were not observed in any of the tumors. In biphasic synovial sarcoma, the neoplastic spindle cells are generally more numerous and frequent than the epithelial cells, making distinction from monophasic synovial sarcoma or other spindle cell soft tissue tumors difficult. Although synovial sarcoma may be diagnosed by fine-needle aspiration cytology, clinical correlation, especially in monophasic types, is necessary to minimize errors in sarcoma classification.

myc protooncogenes of wool and hair growth.

The growth of hard keratin fibers such as wool and hair is dependent on the proliferation of cells in the follicle bulb. If the cells leaving the bulb could be induced to undergo an extra division, then fiber growth should increase. The cellular division within the follicle is complex and probably involves one or more growth factors, which act by altering the expression of transcription factors and other nuclear proteins. We propose that the expression of the myc protooncogenes is a central part of this mechanism. In support of this hypothesis we have detected the mRNAs for TGF-beta 1, basic FGF, TGF-alpha, and c-myc in plucked wool follicles using PCR amplification. We have also shown that the TGF-beta 1, TGF-beta 2, TGF-beta 3, EGF, TGF-alpha, basic FGF, N-myc, and c-myc genes are expressed in mouse skin, and we looked for changes during the hair cycle. The PCR data suggest that in whole skin the levels of mRNA for TGF-beta 1, TGF-beta 2, TGF-alpha, and c-myc do not change. In Quackenbush mice the levels for N-myc, TGF-beta 3, and basic FGF mRNA appear to be lower at the end of the hair cycle. We have confirmed in CBA/C57 black mice that lower levels of N-myc mRNA are detected when hair growth ceases in catagen and telogen. To test our hypothesis further and to assess its practical application, we are making transgenic mice in which the N-myc gene is overexpressed in the hair follicle by way of a wool keratin promoter. The transgene consists of 3.3 kb of 5' sequence from an ovine type 1 IF gene, the murine N-myc genomic coding sequence, and an SV40 polyadenylation signal. The native keratin type 1 IF gene is expressed exclusively in the wool follicle, as shown by in situ hybridization. However, in mice the injection of the transgene has resulted in high embryonic mortality and some embryos with large body size and head malformations. Since these mice were not transgenic, this is likely to be an effect of transient expression of the transgene during embryogenesis. The two transgenic mice produced so far have a normal phenotype.

Imaging of the total knee arthroplasty.

We have reviewed the essentials of TKA imaging. Because the purpose of a knee arthroplasty is to relieve pain and improve function, radiographs should be viewed in the context of these goals.

Extramedullary porous coating to prevent diaphyseal osteolysis and radiolucent lines around proximal tibial replacements. A preliminary report.

Nineteen patients who had a primary malignant bone tumor of the proximal end of the tibia were managed with wide resection and implantation of a tibial endoprosthesis with cement, combined with a rotating-hinge knee replacement. In the first ten patients, a ring of porous coating was applied to the part of the tibial replacement that was just proximal to the intramedullary portion of the stem, to encourage ingrowth of bridging bone. No growth of bone into these porous rings occurred, and the rings were not applied to the next nine endoprostheses. During the subsequent follow-up period, progressive osteolysis (resorption of more than two millimeters of the proximal end of the remaining tibial cortex) developed in only one patient (who had a deep infection) in the group of ten patients who had a porous ring, compared with five of the nine patients who did not have a porous ring but in whom osteolysis developed. This difference was significant (p < 0.001). In addition, the tibial osteolysis was associated with the subsequent development of progressive periprosthetic radiolucent lines at the bone-cement interfaces (p = 0.001). We postulated that, in the patients who had an extramedullary porous ring, the periprosthetic fibrous capsule that formed around the extramedullary portion of all the implants became firmly adherent to the ring, thereby sealing off the part of the capsule that was distal to the ring. The particulate wear debris that was contained within the articular portion of the capsule could not reach the distal tibial bone surrounding the prosthetic stem, and debris-incited osteolysis, which leads to loosening, did not develop. If this mechanism is confirmed, it could have important implications for the design of implants that are used in joint replacement.

Growth factor expression in skin during wool follicle development.

A variety of growth factors are likely to be involved in initiation and morphogenesis of wool follicles. To enable direct comparisons of the expression of different growth factors, reverse transcriptase-polymerase chain reactions (RT-PCR) were developed for ovine and murine TGF alpha, TGF beta 1, TGF beta 2, TGF beta 3, IGF1, IGF2, and FGF-2, which could all be carried out on a single cDNA sample. These RT-PCR were used with 16 sheep RNA samples from different foetal stages, neonatal sheep and mouse skin. The mRNAs for these growth factors were detected throughout gestation in sheep skin, except for TGF beta 1 mRNA which was not expressed in 51-day-old skin, but was expressed in 54-day and older samples. Since the first microscopically visible changes of follicle initiation occur around 62 days gestation, these results suggest that TGF beta 1 expression may be a signal for follicle initiation.

Loose fragments and other debris: miscellaneous synovial and marrow disorders.

Conventional MR imaging evaluation of the knee focuses mainly on the effects of acute trauma and degenerative conditions. Numerous other conditions that affect the knee may mimic clinical characteristics of common traumatic and degenerative disorders. Synovial and marrow abnormalities are frequently encountered and often unsuspected on routine MR imaging studies of the knee. This article presents the MR imaging appearance of the normal synovium, bone marrow, and commonly encountered abnormalities of these structures.

Medical management of metastatic skeletal disease.

The medical management of metastatic disease generally includes chemotherapy, hormonal therapy, and metabolic pharmacologic manipulations with medications, such as bisphosphonates as well as nonoperative physical measures, such as orthoses and ambulatory or mobility aids. This comprehensive complex care is best coordinated with the medical oncologist. If well planned and coordinated, such care can improve the life of the cancer patient greatly.

Endoprosthetic bone reconstruction following malignant tumor resection in skeletally immature patients.

Modular and expandable endoprosthetic reconstruction of the child's extremity following bone tumor resection affords an opportunity for both limb salvage and progressive limb length equalization. This article discusses the rationale, advantages, disadvantages, and results of endoprosthetic bone reconstruction following tumor resections in the skeletally immature patient. In addition to an extensive literature review, an overview of the authors' results with this reconstructive option in 31 patients over the past 14 years is presented. This article will inform the reader of the current state of the art in endoprosthetic reconstruction of the immature patient and should allow clinicians to make more informed decisions regarding treatment options for their patients.

Metastatic disease of the femur. Surgical management.

Treatment of actual or impending pathologic fractures of the femur provides the senior author with some of the most rewarding surgical interventions of his practice. The patients' survival outlook is not changed, but their quality of life is enhanced significantly. Most health care providers usually provide the metastatic cancer patient only temporary symptomatic relief, at best, and often at the expense of continued pain, suffering, or sickness, such as is seen with chemotherapy-associated morbidity. Patients with metastatic bone disease are usually incredibly grateful for the restoration of function and diminution of their pain that results from the proper operation on metastatic bone disease. These patients typically are among the most appreciative patients and often express their gratitude when seen in follow-up in the clinic or office. Despite their metastatic disease state, their usual enthusiasm is uplifting to the surgeon and to the staff. To help a patient be pain-free and functional in the waning days of his or her life affords the patient, the physician, and the physician's staff with an emotionally rewarding experience and one that is well worth the time and effort required to care for these patients. By following the techniques outlined in this article, most patients with metastatic disease of the femur can be appropriately managed with excellent results.

The use of vacuum-assisted closure therapy for the treatment of lower-extremity wounds with exposed bone.

Lower-extremity wounds with exposed tendon, bone, or orthopedic hardware present a difficult treatment challenge. In this series of patients, subatmospheric pressure therapy was applied to such lower-extremity wounds. Seventy-five patients with lower-extremity wounds, most of which were the result of trauma, were selected for this study. Dressings made of sterile open-cell foam with embedded fenestrated tubing were contoured to the wound size and placed into the wound. The site was covered with an adhesive plastic sheet. The sheet was placed beneath any external fixation devices, or the fixation device was enclosed within the sheet. The tubing was connected to the vacuum-assisted closure pump. Continuous subatmospheric suction pressure (125 mmHg) was applied to the wound site. The wounds were inspected and the dressings were changed every 48 hours.Vacuum-assisted closure therapy greatly reduced the amount of tissue edema, diminishing the circumference of the extremity and thus decreasing the surface area of the wound. Profuse granulation tissue formed rapidly, covering bone and hardware. The wounds were closed primarily and covered with split-thickness skin grafts, or a regional flap was rotated into the granulating bed to fill the defect. Successful coverage was obtained without complication in 71 of 75 patients. Wounds have been stable from 6 months up to 6 years.

Occult orthopaedic trauma in the multiply injured patient.

A retrospective review of 111 multitrauma patients revealed that of 401 orthopaedic injuries, 24 injuries (6%) were not initially diagnosed in 20 patients. Patients with occult injuries tended to have greater overall trauma, as reflected by lower trauma and lower Glasgow coma scores and longer hospital and intensive-care unit stays. Twenty prospectively identified cases were added to the series to further define risk factors. Seventy percent of occult bony injuries were ultimately diagnosed by physical examination and plain radiographs alone. Only 27% of cases required sophisticated imaging techniques for diagnosis. Based on these 44 cases of occult injuries in multitrauma victims, the following risk factors were identified: (1) significant multisystem trauma with another more apparent orthopaedic injury within the same extremity, (2) trauma victim too unstable for full initial orthopaedic evaluation, (3) altered sensorium, (4) hastily applied emergency splint obscuring a less apparent injury, (5) poor quality or inadequate initial radiographs, and (6) inadequate significance assigned to minor signs/symptoms in a major trauma victim. Due to the nature and extent of the overall trauma, all injuries cannot be diagnosed on initial patient evaluation.

Concomitant fractures of the capitellum and radial head.

Seven cases of coexisting capitellum and radial head fractures are reported. Our best results were obtained when early open reduction and internal fixation (ORIF) of the larger, more suitable fracture was combined with excision of the smaller fracture fragments and the early initiation of motion. Poor results were obtained when there was (a) incomplete removal of intraarticular fragments, (b) associated medial collateral ligament injuries, or (c) when ORIF was attempted on small capitellum fracture fragments.

Myxofibrosarcoma of soft tissues: cytomorphologic analysis of a series.

Within the English literature, myxofibrosarcoma is a recently described entity. Although the histopathologic features have been reported, the cytomorphologic spectrum of myxofibrosarcoma has been far less documented. The cytologic findings of six fine-needle aspiration biopsy specimens (five primaries, one local recurrence) from six patients are described. The patients' ages ranged from 26-77 yr; there were four women and two men. The aspiration biopsy specimens ranged from slightly to markedly cellular. Although a myxoid granular to filamentous background was observed at least focally in all cases, the volume of the myxoid material was inversely proportional to the cellularity and grade of the tumor. Individual tumor cells were round to spindled, often displaying a wide range of cell shapes and sizes. Nuclei were generally large, pleomorphic, and hyperchromatic, frequently containing prominent nucleoli. Cytoplasm ranged from scant to dense and tapering. Multinucleated tumor giant cells were occasionally observed. In general, low- and intermediate-grade myxofibrosarcomas were more easily recognized in cytologic preparations. In contrast, high-grade myxofibrosarcoma was more difficult to specifically subtype and not easily distinguished from other adult pleomorphic sarcomas.

Malignant peripheral nerve sheath tumor: a fine-needle aspiration biopsy study.

Although the histopathologic features of malignant peripheral nerve sheath tumors (MPNST) have been well-described, the cytologic features are less well-characterized. We retrospectively reviewed 4 aspiration specimens from 3 patients with histologically-proven MPNST. The biopsy specimens were obtained from the primary tumor (1 case), a local recurrence (2 cases), and a pulmonary metastasis (1 case). The patients were women, aged 42, 61, and 70 yr. The primary tumors arose from the left neck and elbow, and from a neurofibroma in the right medial thigh. The latter patient had von Recklinghausen's disease. Cardinal cytomorphologic features included aggregates and single cells with ovoid to elongated, and comma to serpentine shapes, as well as hyperchromatic nuclei surrounded by delicate, tapering cytoplasm. Nuclear pleomorphism ranged from slight to marked. Multinucleated giant cells were seen in 2 cases. In general, the degree of nuclear variability within each individual case exceeded that typically observed with synovial sarcoma or fibrosarcoma. Although the cytomorphologic features may strongly suggest MPNST, clinical correlation is necessary and immunocytochemistry (i.e., S-100 protein) may help to distinguish MPNST from other spindle-cell sarcomas. Origin from a nerve trunk or preexisting neurofibroma, or occurrence in a patient with von Recklinghausen's disease, confirms the diagnosis of MPNST.

Epithelioid hemangioendothelioma of bone and soft tissue: a fine-needle aspiration biopsy study with histologic and immunohistochemical confirmation.

We retrospectively reviewed two fine-needle aspiration biopsy (FNAB) specimens from two patients with histologically confirmed epithelioid hemangioendothelioma (EH). Both patients were men, ages 79 and 39 years; their primary tumors arose in the soft tissues of the mediastinum and within the proximal tibia, respectively. The former patient had symptoms of superior vena cava syndrome; multicentric intraosseous lesions involved the proximal tibia of the latter patient. All cytologic smears were hypercellular and composed of mostly disassociated single cells and small aggregates of ovoid to polygonal-shaped epithelioid cells. Nuclei were variable, ranging from ovoid and reniform to round and polylobated and surrounded by an abundant amount of dense cytoplasm. Binucleated epithelioid neoplastic cells were frequent. Nuclear pleomorphism ranged from slight to moderate, and small solitary to multiple nucleoli were identified within the majority of tumor cells. Rare neoplastic cells with a single, sharply demarcated intracytoplasmic vacuole and intranuclear cytoplasmic pseudoinclusions were observed in the smears of one tumor. Metachromatic stromal fragments, probably representing hyalinized chondromyxoid stroma, were seen in the other tumor. Neither case was recognized initially on FNAB as EH. Immunohistochemically, sections from the surgical biopsy specimens of both cases showed diffuse and strong immunopositivity for the endothelial marker CD31. Although the cytomorphology of EH appears distinct, clinicoradiologic correlation is essential, and immunohistochemistry may be helpful to avoid misdiagnoses.