Alexander D Rapidis. Expert Review of Anticancer Therapy. Volume 8, Issue 8. Aug 2008.
Sarcomas comprise a heterogeneous and biologically diverse group of malignant neoplasms having as a common denominator their origin from mesenchymal cells. They constitute less than 1% of all malignancies and so do those in the head and neck region. The most common histologic types of head and neck sarcoma are osteosarcoma and pleomorphic sarcomas (malignant fibrous histiocytoma [MFH]), each accounting for up to 20% of all cases.
Sarcomas may occur in any anatomical site of the human body but they show a predilection for the upper and lower extremities, with 40% of all sarcomas occurring in the lower limb and 20% in the upper limb, whereas approximately 20% of sarcomas occur in the retro- and intraperitoneal sites and 10% in the trunk. The head and neck is the site of up to 10% of all sarcomas.
Traditionally, sarcomas have been classified according to a histogenetic concept: for example, fibrosarcoma as a tumor arising from fibroblasts and osteosarcoma as a tumor arising from osteoblasts. Morphologic, immunohistochemical and experimental data though suggest that most, if not all, sarcomas arise from multipotential mesenchymal cells, which in the course of neoplastic transformation undergo differentiation along one or more lines. Until recently, the clinical importance of histological typing and subtyping of soft-tissue sarcomas (STSs) was minor, since their treatment depended more on grade, stage and operative considerations in relation to the site. The main role of histopathological examination of the lesions was to exclude other types of malignancy and to perform a grading. Grading has been recognized in many studies as the most important histopathological prognostic factor. Accurate determination of prognosis is critical in order to guide therapeutic decisions and provide systemic therapy for patients whom it will benefit. Over the last few decades, it has become clear that the primary factor in predicting metastasis and death from disease is histological grade and, for this reason, clinicians and pathologists have focused on the accuracy and reproducibility of various grading systems. Grading identifies patients at greatest risk of distant metastasis and more prone to benefit from chemotherapy, and plays an ancillary role in allowing comparisons in clinical trials.
The last 20 years have witnessed significant advances in the histological diagnosis of STSs, mainly with regard to the application of immunohistochemistry. There are over 50 types and subtypes of sarcomas, which are currently diagnosed by genetic and morphological criteria. The optimal tumor classification is one that assures a reproducible diagnosis that is also clinically useful. Whether these goals are best reached by morphology or genetics can be discussed, since both have their limitations. The molecular classification of cancer has recently been prompted by the sequencing and annotation of the human genome project and technical advancement in gene transcription profiling. These profound scientific advancements have permitted high-throughput analysis and molecular correlation between tumors, which provides insight into molecular pathways and mechanisms. Techniques such as PCR, reverse transcriptase-PCR, FISH and comparative genomic hybridization (CGH) are being commonly used to detect alterations at the molecular level. As for most other cancers, these alterations can result in either gain or loss of important gene function. The two main pathways are the p53 tumor suppressor pathway and the retinoblastoma (RB) oncogene pathway, but new candidate genes are being constantly reported. The identification of a significant number of translocation-associated sarcomas has resulted in an optimistic search to correlate translocation type with outcome. The potential value of various tumor characteristics at the DNA and protein levels of sarcomas have been studied and most of the reported results for novel prognostic markers have either been disputed by discordant results or have not been substantiated in independent patient series. The classification of sarcomas will continue to evolve as additional subtypes of this disease are introduced into the molecular classification scheme. More detailed analysis of the gene expression profiles of each of the more than 50 subtypes of STSs will clarify the biological differences within STS and will hopefully propose therapies specific for each subclass of STS, if not therapy specific for an individual patient’s tumor. In a number of sarcomas of the head and neck, clinical parameters, such as anatomic location, extent of disease, age and comorbidities, are of equal importance in determining prognosis.
Occurrence of Sarcomas in the Head & Neck Region
The incidence of sarcomas among malignant tumors of the human body does not exceed 1%. It is estimated that approximately 9000 new cases are seen yearly in the USA. In 1996 the American College of Surgeons published a National Cancer Data Base Report on STSs. In this report they compared findings from a previous study in 1988 in which 3500 new cases of STSs were included, whereas in 1993 this number rose to 4252. It is clear that the annual number of reported cases of sarcomas is rising worldwide. This can be attributed to two factors: either the absolute number of cases of sarcomas is rising annually or sarcoma cases are reported to cancer registries more accurately. What makes sarcomas of the soft and hard tissues interesting is their diverse histopathology and their resistance to medical treatment. Sarcomas, in general, remain a disease cured primarily with surgery, despite the advances of both radiotherapy and chemotherapy during the last 30 years.
The occurrence of soft and hard tissue sarcomas in the head and neck area is approximately 10% of all sarcomas. In the study of the American College of Surgeons, STSs of the head and neck were reported to be 13.7% in 1988 and 11.4% in 1993. From the malignant tumors of the head and neck area sarcomas represent 1% of all malignancies. The frequency of each clinicopathological entity of the 50-100 different types varies among the reported case series. Large series of head and neck sarcomas have been reported in the literature from Memorial Sloan Kettering Cancer Center in New York, MD Anderson Cancer Center in Houston Texas, the University of California Los Angeles Medical Center and others. Pleomorphic sarcoma or MFH appear to have the highest prevalence in STSs of the head and neck, with fibrosarcoma and angiosarcoma following in frequency in the adult population. Rhabdomyosarcoma and Ewing sarcoma are the most frequently encountered sarcomas in the pediatric population. Osteosarcoma has the highest incidence among bone sarcomas in both the pediatric and adult population. There are some histological variants of sarcomas that present solely in the head and neck area. These include odontogenic sarcomas and a variant of malignant peripheral nerve sheath tumor called the Triton’s tumor.
The reason for the interest in head and neck sarcomas lies not in their difference in biologic behavior and tumor histology, but in the difficulties encountered during their surgical treatment in respect of their counterparts of the limbs, trunk and retro- and intraperitoneal sites. The anatomy of the head and neck is perhaps the most complex of the human body with several sensitive anatomical elements present. During surgical treatment of sarcomas, generous disease-free margins are required for the extirpation of the disease and this is the gold standard of treatment. In the head and neck safe surgery may include large segments of the craniofacial skeleton, leaving surgical defects that impede function and cosmesis of the patient. The indolent, on the other hand, course of disease of the sarcomas produce, in the majority, minimal clinical signs and symptoms, thus making an early diagnosis extremely difficult or impossible. Additionally, the clinical suspicion index of any examining physician toward the diagnosis of a head and neck sarcoma is low due to their scarcity.
Diagnosis can only be achieved after histological examination of a biopsy specimen. Whether this would be an open biopsy or a true cut lies with the examining physician and should take into consideration the possibility of tumor spillage and seeding of the tumor to the adjacent structures during open biopsy. Fine needle aspiration (FNA) biopsy has recently been evaluated, after diagnostic imaging, as one of the first procedures to be performed in a patient presenting with a soft-tissue mass in the head and neck area. In the diagnosis of sarcomas, FNA has been found to achieve a sensitivity of 94%, a positive predictive value of 97% and an overall accuracy of 91%. One of the criticisms of FNA biopsy is that even if sarcoma is diagnosed, grading is not provided, but it should be safely used to diagnose local disease recurrence or metastasis.
Sarcomas of the head and neck are classified into soft-tissue, bone and cartilage, hematolymphoid, neuroectodermal and odontogenic sarcomas. A separate group is the radiation-induced sarcomas (RIS).
Malignant Soft-tissue Tumors
Two synonyms are fibromyxosarcoma and chondromyxofibrosarcoma. Fibrosarcoma is generally defined as a malignant mesenchymal tumor with cells recapitulating the appearance of normal fibroblasts. Fibrosarcoma accounts for approximately 15% of all STSs. They are considered the second most common STS after rhabdomyosarcoma in the head and neck. They occur in all ages, with a peak in the fifth decade. There is a 3:2 female:male gender predilection. Frankenthaler et al. found 118 fibrosarcomas of the head and neck region, with the neck being the most common site, followed by face, scalp and maxillary sinus. Only 12% of the fibrosarcomas were located intraorally, approximately half of them in the mandible.
The clinical behavior of the fibrosarcoma is characterized by a high local recurrence rate and a low incidence of locoregional lymph node and/or distant hematogenous metastases. When present they may involve the lungs, mediastinum, abdominal cavity and bone. Local recurrences and distant metastases in fibrosarcoma show a wide variability, with the local recurrence rate being between 9 and 75% and distant metastases between 6 and 58% of patients. Especially in recent reports, prognosis has been shown to be more favorable than previously thought of.
Following the development of immunohistochemical and cytogenetic methods, numerous tumors formerly diagnosed as fibrosarcomas were reclassified as other malignant soft-tissue tumors. Thus, conventional fibrosarcoma has become a diagnosis of exclusion. Immunohistochemically, tumors with myofibroblastic differentiation can display several phenotypes because myofibroblasts share characteristics with both fibroblasts and smooth muscle cells. Fibrosarcomas are always positive for vimentin and can also present immunopositivity for desmin, muscle-specific actin and smooth muscle myosin heavy chain.
Wide local excision remains the treatment of choice. Radiotherapy is mandatory when adequate surgical margins cannot be obtained and a reoperation is not possible. Poor prognostic factors include male sex, large tumor size, involvement of more than one contiguous site (nasal cavity and sinus, multiple sinuses), high histologic grade and positive surgical margins.
Pleomorphic sarcoma or so-called malignant fibrous histiocytoma
Some synonyms are fibroxanthosarcoma, malignant fibrous xanthoma, myxofibrosarcoma, myxoid MFH. MFH has been regarded as the most common STS in adult life but it has been overwhelmed by controversy in terms of both histogenesis and validity as a clinicopathological entity. MFH was recognized as one of the most common STSs in adults. MFH was introduced in the 1960s to describe a group of lesions presumably derived from a mixed histiocytic and fibroblastic lineage. Brooks and, later, Dehner were the first to suggest that MFH represented a common pathway of tumor progression for a variety of other well-defined entities, rather than a distinct tumor entity. Several other subsequent studies using immunohistochemistry, cytogenetics and molecular diagnostics reexamined MFH and reported that most of the previously diagnosed MFH shared clinicopathologic features with other better characterized lesions. Fletcher et al. in two different studies, one comprising 159 cases of MFH and the other 100, showed that 63% of MFH cases could be reclassified as other sarcomas and 13% were in fact nonmesenchymal neoplasms. Oda et al. studied 428 MFH and found that 32% of these cases could be better classified as other mesenchymal and nonmesenchymal tumors. These and a number of other reports question whether MFH show fibroblastic or histiocytic differentiation and that it might be necessary to improve diagnostic reproducibility and tumor grading to further understand the tumor biology. It is therefore questionable whether MFH is a distinct clinicopathological entity or should be eliminated and replaced with the term pleomorphic sarcoma. However, a recent WHO classification of tumors of soft tissue and bone includes the term MFH as a synonym for pleomorphic sarcoma. In addition to soft tissue, MFH can also occur as a primary intraosseous tumor in bones. It affects, in order of frequency, the lower extremity, the upper extremity, the retroperitoneum and abdominal cavity, and the head and neck, where it accounts for 1-3% of all cases.
The composition of MFHs includes an admixture of fibroblastic, histiocytic and undifferentiated cells arranged in a storiform growth pattern. The undifferentiated cell may represent a progenitor with capacity to differentiate into histiocytic and fibroblastic cells but the relationship between histiocytic-like cells and true macrophages/histiocytes remains debatable.
Undifferentiated pleomorphic sarcomas or pleomorphic MFH are a group of high-grade sarcomas that cannot be classified otherwise. They develop in patients of advanced age and particularly in damaged skin. Men appear to be affected more often than women. All the subtypes of MFH occur in patients between the ages of 50 and 70 years.
In the head and neck, the majority of MFH cases are of the storiform-pleomorphic or myxoid variants. These tumors occur most commonly in the region of the sinonasal tract, craniofacial bones, larynx, soft tissue of the neck, major salivary glands and the oral cavity. The most common presentation is that of a painless enlarging mass. MFH gives images that are inhomogeneous in appearance on CT scans and show high signal intensities on T2-weighted MRI images.
Surgery is the treatment of choice for MFH. Wide resection of the tumors located in the head and neck region with adequate margins of normal surrounding tissues is required for a favorable prognosis. Although MFH appears to be grossly encapsulated, attempts at simple enucleation result in recurrence in almost half of the cases. This is due to the fact that MFH demonstrate microscopic spread along the fascial planes and muscle fascicles, beyond the confines of the presumed capsule. Therefore, a wide excision of these tumors is mandated. Because regional lymph nodes are involved in only 10-18% of cases, consideration should be given to elective neck dissection for patients with advanced-stage disease or evidence of aggressive histopathology. Huvos et al. mention that metastatic spread in patients with MFH primary in bone is not regional lymph nodes but rather hematogenous dissemination predominantly to the lungs.
Radiotherapy alone or chemotherapy alone is not effective for MFH of the head and neck region. The decision of whether to submit a patient to radiation therapy depends on the size, site, histologic grade and width of surgical margins. Chemotherapy has been used in patients with a predictably high risk of pulmonary metastasis. The administration of anticancer agents, such as methotrexate, cisplatin, doxorubicin, cyclophosphamide, actinomycin-D, vincristine, dacarbazine and ifosfamide, has been reported in patients with STS. However, tumoricidal effectiveness of each drug is limited to a single administration. It is therefore important to select multiagent combination therapy, considering the interaction of these agents. If chemotherapy is to be used, treatment regimes should include adriamycin, since it has been shown to be effective for MFH.
Survival is reported to be 60% at 2 years, with a high incidence of recurrence (44%) and metastasis (44%). The proportion of local recurrence rates of MFH after initial local excision ranges between 16 and 52%. Distant metastases of MFH are common and can occur via hematogenous or lymphatic spread. The presence of positive surgical margins after definitive treatment is the single most important factor relating to local recurrence. According to Barnes and Kanbour, 80% of patients with local recurrences after incomplete surgical treatment subsequently die from disease.
Leiomyosarcomas are smooth muscle tumors that most frequently occur in the uterine myometrium, the GI tract and the retroperitoneum. The skin and subcutaneous tissues are other less frequent sites. Occurrence in the head and neck is considered rare, probably because of the paucity of smooth muscle tissue. The source of smooth muscle tumors in the oral cavity may be the arterial tunica media, the ductus lingualis, the circumvallate papillae and pluripotential mesenchymal cells. Oral leiomyosarcomas do not display any significant gender predilection and occur over a wide age range, with most patients in their third, sixth and seventh decade of life. The jawbones appear to be the site of predilection for oral leiomyosarcomas. Approximately 70% of these tumors arise in the maxilla or mandible. Other intraoral locations include the tongue, cheek, gingiva, soft palate, upper lip and floor of mouth. In several cases, leiomyosarcomas originated from neurovascular bundles of the facial bones. Primary head and neck leiomyosarcomas appear microscopically as spindle cell neoplastic proliferations. The tumor cells are arranged in an interlacing fascicular pattern and contain oval to elongated, blunt-ended (cigar-shaped) nuclei. The nuclei may demonstrate hyperchromatism and varying degrees of atypia and pleomorphism. Mitoses may vary in number from infrequent to abundant. The cytoplasm of the tumor cells stains intensely with eosin because of its content of smooth muscle actin-myosin bundles. It also stains red with Masson’s trichrome and contains PTAH-positive myofibrils. Cytoplasmic glycogen-laden granules in many of the cells stain positive with periodic acid-Schiff stain. Myxoid changes and necrosis may be encountered in the stroma. Other cell populations that may be found occasionally coexisting with the spindle cells are multinucleated giant cells, histiocyte-type cells and epithelioid cells. Oral leiomyosarcomas may be graded histologically depending on the number of mitoses observed per ten high-power fields, the cellular atypia and pleomorphism encountered or other indicators of invasiveness. Grade I represents a low-grade tumor, whereas grade III represents a high-grade tumor with aggressive biologic behavior. Surgical excision seems to offer the best outcome provided there is complete removal of the tumor. The favorable long-term outcome of patients is attributed to the radical approach that is employed in the surgical management of the primary site.
Leiomyosarcomas are generally considered radioresistant. Some reports have suggested a beneficial effect in terms of decreased recurrence, increased survival and the possibility of less radical surgery, but these differ from the uniformly poor response to radiotherapy used either as a primary or adjuvant method of treatment in oral leiomyosarcomas. Chemotherapy is usually used as a palliative modality for inoperable lesions and metastatic disease.
The reported incidence of local recurrence for oral leiomyosarcoma is 34% and differs from tumors originating from the superficial soft tissues (50%), retroperitoneum and blood vessels (50%). The frequency of distant metastasis in oral leiomyosarcoma is 35%. The lungs are the most frequent site of metastasis. The estimated 5-year survival is reported to be 55%. Multivariate analysis of a cohort of 225 patients with leiomyosarcomas of all sites showed that higher malignancy grade, larger tumor size and deeper tumor location were correlated significantly with decreased metastasis-free and overall survival. Tumors demonstrating bony involvement (maxilla/mandible) and metastasis were associated with poorer prognosis. Increasing age and male sex show a trend toward worse prognosis.
Some synonyms are myosarcoma, embryonal sarcoma, malignant rhabdomyoma, rhabdosarcoma, botryoid sarcoma, embryonal sarcoma, rhabdomyoblastoma. Rhabdomyosarcoma is a malignant neoplasm deriving from primitive mesenchymal tissue expressing myogenic differentiation and probably arises from satellite cells associated with skeletal muscle embryogenesis. Rhabdomyosarcoma is the most common STS of childhood and adolescence involving the head and neck region. While only 2-5% of all STSs are rhabdomyosarcomas in adults, this tumor represents approximately 60% of STSs in children. Approximately 35% of all rhabdomyosarcomas arise in the head and neck region. It is subdivided into three major groups: embryonal, alveolar and pleomorphic.
Embryonal and alveolar subtypes of rhabdomyosarcoma are the most common in children and teenagers, while pleomorphic rhabdomyosarcoma is more commonly diagnosed in adults. The alveolar variant of rhabdomyosarcoma is relatively rare compared with the other histologic types. The head and neck region, including the oral cavity, parotid gland, nasopharynx and nasal cavity, is the most commonly affected area, accounting for 50% of the cases. Patient age ranges from 18 to 79 years (median: 32 years). Embryonal rhabdomyosarcoma has been characterized by a consistent loss of heterozygosity (LOH) or loss of imprinting at a specific locus on the short arm of chromosome 11 (11p15). This cytogenetic abnormality occurs in a high percentage of embryonal rhabdomyosarcomas and is also found with other childhood malignant tumors, such as Wilms tumor and hepatoblastoma. Histologically, embryonal rhabdomyosarcoma has round to spindled cells with hyperchromatic nuclei. Larger rhabdomyoblasts with eosinophilic cytoplasm are usually identified. The botryoid variant is polypoid with a submucosal hypercellular cambium layer, a myxoid hypocellular zone and a deep cellular component.
Alveolar rhabdomyosarcoma typically has fibrous septa separating clusters of loosely cohesive groups of small-to-medium round tumor cells with hyperchromatic nuclei and scant eosinophilic cytoplasm. The vast majority of rhabdomyosarcomas will immunoreact with polyclonal desmin and myogenin. A small proportion may represent undifferentiated sarcomas and require vimentin, as well as other markers to rule out other small round cell tumors of childhood. Expression of the mutated p53 protein may be detected by immunocytochemistry and has been linked to decreased survival, less favorable outcome and anaplastic tumors. Cytogenetic and molecular genetic studies are important to confirm the alveolar rhabdomyosarcoma type.
Rhabdomyosarcoma is, in general, treated according to specific chemotherapy protocols. The main chemotherapeutic agents include vincristine, dactinomycin and cyclophosphamide. Adults have a poor prognosis, with 5-year survival of less than 10%. Older patients with pleomorphic histology have a better survival rate compared with younger ones. The biologic factors that determine this behavior remain unknown. Embryonal rhabdomyosarcoma has a better prognosis than alveolar rhabdomyosarcoma. Botryoid and spindle cell variants have a better prognosis than embryonal rhabdomyosarcoma. The reasons for this apparently worse outcome remain to be elucidated, but two possible explanations can be proposed. The first possible reason is that there is less sensitivity to chemotherapy in the adult population, either because these patients are less tolerant to high-dose chemotherapy or because the neoplasms are less chemosensitive. The second possibility is that the tumors arising in the head and neck are less amenable to appropriate surgical resection with wide margins. Hence, residual viable tumor probably gives rise to local recurrences, which are difficult to control. With the use of multimodal therapy, including surgery, and multiagent chemotherapy with or without radiation therapy, the cure rate for localized rhabdomyosarcoma has nearly tripled since 1970 from 25 to over 70%. Although chemotherapy has been used for systemic disease, the preferred local therapy is complete resection without loss of form and function, complemented by radiotherapy in selected cases. The result of surgical treatment and especially the status of surgical margins have led to the development of a classification system for patients treated by surgery. Complete resections are classified as group I, microscopically positive margins are classified as group IIa, resected positive regional lymph nodes as group IIb and IIc, and microscopically residual tumors as group III. Adjuvant radiotherapy is recommended in group II and III patients. Omission of radiotherapy in the primary treatment may be considered in patients with favorable histology where the side effects from radiotherapy would be severe, such as in very young patients and in those presenting with tumors in particularly sensitive sites. Prognosis is determined by five independent variables, which include invasiveness, metastasis, age at diagnosis, regional node involvement and histopathologic subtypes. Age exerted its greatest effect on patients with invasive but nonmetastatic tumors.
Some synonyms are malignant hemangioendothelioma, malignant angioendothelioma, lymphangiosarcoma, hemangiosarcoma. Angiosarcomas are rare vascular tumors, the cells of which manifest many of the morphologic and functional properties of normal epithelium. They may vary from highly differentiated tumors to those with significant anaplasia, sometimes making these tumors difficult to differentiate from melanomas or carcinomas. Angiosarcoma is a malignant neoplasm, more frequently occurring in the skin and subcutis or in visceral location. Angiosarcoma of the head and neck is a rare vascular tumor most frequently found on the face and scalp. Angiosarcomas constitute only 2% of all sarcomas. There is a trend for patients of over 50 years of age to have a worse clinical outcome than patients who are younger in age. They present in the skin of the face and neck as red plaques and nodules, which may be extensive and tend to ulcerate. The oral cavity is an extremely rare site for such tumors. Clinically, intraoral angiosarcomas have been reported as painful, spontaneously bleeding, round or ovoid nodules that appear red to bluish in color and firm on palpation, and some of them can ulcerate the overlying oral mucosa. A size of 4 cm or larger correlates with poor prognosis. Morphologically, this unencapsulated tumor consists of haphazardly arranged endothelial cells, sometimes displaying intracytoplasmic vacuoles containing red blood cells, enclosing irregular luminal spaces that resemble abortive vascular channels. The endothelial cells may show variable degrees of pleomorphism, along with spindle cell and epithelioid features. Angiosarcomas may show a wide spectrum of histologic differentiation, from well-differentiated neoplasms showing anastomosing vascular channels lined by atypical endothelial cells with scant mitotic activity, to poorly differentiated tumors without prominent vasoformative activity, composed of solid sheets of epithelial-like or spindle cells. A clue for the diagnosis of poorly differentiated angiosarcoma is the accurate identification of intracytoplasmic vacuoles containing intact or fragmented red blood cells. All cases demonstrate immunoreactivity with antibodies to Factor VIII-RA, CD34, CD31 and smooth muscle actin. Epithelial membrane antigen and muscle-specific actin show varied immunoreactivity. Surgical resection with radiation and/or chemotherapy is the treatment of choice. Achieving negative surgical margins is often impossible due to the subclinical extension of the tumor into healthy-appearing tissues.
In a series of 28 patients who underwent surgical resection for angiosarcoma of the scalp only six (21.4%) had negative pathologic margins at the completion of their surgeries. Although frozen section margins performed intraoperatively may assist in determining the extent of the resection, permanent histology may still show positive margins. The reported intraoperative frozen sectioning sensitivity is 65%, with a positive predictive value of 100% but a negative predictive value of only 33%. Angiosarcoma manifests an aggressive clinical course and has a poor prognosis, even in cases with complete surgical removal of the tumor, and does not usually benefit from radiochemotherapeutic regimes. Recently, paclitaxel and docetaxel have been used in metastatic angiosarcoma with promising results. Recurrences develop in a third of patients. VEGF is overexpressed in 80% of human angiosarcomas.
VEGF promotes vascular endothelial growth and induces endothelial migration, promotes cell survival and increases vascular permeability. It also mediates radioresistance. Anti-VEGF therapies have been found to suppress growth and act synergistically with radiation in many human tumor lines. The combination of bevacizumab with preoperative radiation in the treatment of angiosarcoma is under research.
Liposarcoma is a malignant growth of fat cells. The presumed origin of liposarcoma from totipotential primitive mesenchymal cells may be reflected in the wide variety of cell types that compose these tumors and include mucoid lipoblasts, immature, mature and well-differentiated lipocytes or signet ring cells, mulberry cells with a round central nucleus and many cytoplasmic vacuoles, and bizarre giant cells. It most commonly presents in the deep soft tissues of the retroperitoneum, lower limb and shoulder, and fewer than 1% present intraorally. Head and neck liposarcomas are rare and a review of the literature disclosed less than 100 cases. Intraoral liposarcoma accounts for a third of the cases found in the head and neck. Of these, the most common anatomic location is the buccal mucosa. Most liposarcomas present between the ages of 40 and 60 years, and they rarely occur before the age of 30 years. There is a slight male predilection. The most commonly reported symptom was that of a slowly growing, painless mass or swelling.
The WHO divided liposarcomas into five main types: well-differentiated, myxoid, round cell, pleomorphic and dedifferentiated. The most important predictor of the clinical behavior of liposarcoma is histologic type. However, difficulty in classifying liposarcomas by light microscopic criteria has prompted several authors to identify prognostic markers through cytogenetic and molecular analyses. Myxoid and well-differentiated liposarcomas have much more favorable 5-year survival rates than round cell and pleomorphic types. Other factors influencing survival rate are tumor location and completeness of surgical excision. Wide surgical excision is the treatment of choice. Complete excision is usually sufficient to cure low-grade tumors (well-differentiated and myxoid). Incomplete excision of the pseudoencapsulated tumor may lead to recurrence. Patients with high-grade tumors may develop metastases years later. Nonsurgical treatment modalities have limited value. Postoperative radiotherapy has not been established to prolong survival. The role of adjuvant or neoadjuvant chemotherapy for high-grade adult sarcomas is still a controversial issue. However, liposarcoma patients receiving first-line chemotherapy for palliation of advanced disease showed a statistically significant higher response rate. Overall 5-year survival is 35% with a 5-year local recurrence-free survival rate of 73%.
Synovial sarcoma (SS) is the fourth most common type of sarcoma, following MFH, liposarcoma and rhabdomyosarcoma, and accounts for 5-10% of all STSs. They are termed SS because of their histologic resemblance to the synovium, but they rarely involve a synovial structure and are thought to arise from pluripotential mesenchymal cells. Approximately 85% of SS are located in the extremities, with 60% in the lower and 25% in the upper limb. SSs do not originate from mature synovial cells and their histogenesis remains controversial. Intercellular junctions, microvilli, external lamina and epithelial differentiation are rarely observed in normal synovium but can be seen in SSs. SS is a highly invasive tumor, with only 3% of all cases occurring in the head and neck region. An increasing number of primary SSs have been detected in oral and maxillofacial sites, including the buccal mucosa, maxillary sinus, mandible, tongue and floor of the mouth. The typical clinical presentation of these lesions is a slow-growing, deep-seated, palpable mass associated with pain in approximately 50% of cases.
SS is not restricted to periarticular sites. It can appear in locations unrelated to the synovium, such as the tongue and soft palate. SS is most prevalent in adolescents and young adults between 15 and 40 years of age. Men appear to be slightly more susceptible than women. There are three subtypes of SS: the biphasic type, consisting of distinct epithelial and spindle cell elements, the monophasic fibrous type, consisting of only spindle cells, and the poorly differentiated type, consisting of poorly differentiated areas of high cellularity, pleomorphism, and polygonal or round-cell morphology, together with frequent mitosis and necrosis.
Although the cell of origin for SS is generally assumed to be an undifferentiated mesenchymal stem cell that undergoes a synovial cell differentiation program after transformation, the mechanisms responsible for development of monophasic and biphasic tumors or the variable proportion of spindle cell and epithelial cell types is poorly understood. Immunohistochemically, the spindle cells of SS strongly and uniformly express mesenchymal marker (vimentin) with occasional evidence of cytokeratin markers, particularly in biphasic tumors. By contrast, the epithelial cells usually demonstrate strong expression of epithelial markers (CK7, CK19, EMA).
Although gene amplification and protein overexpression are closely associated processes, each represents a distinct molecular condition that may occur independently of the other. The cellular and molecular mechanisms defining the clinical behavior of SS are poorly understood. The characteristic translocation t(X;18)(p11.2;q11.2) and its resulting SYT/SSX1 or SYT/SSX2 fusion transcript are the only well-described findings, with SYT/SSX1 conferring a poorer prognosis. Thus far, three SSX genes (SSX1, SSX2 and SSX4 ) have been identified as a partner of the SYT gene, and more than 95% of SS carry one of these fusion genes. Recently it was shown that for patients with localized SS, histology grade but not SYT/SSX fusion type is a strong predictor of survival. Owing to the paucity of cases of SS in the oral and maxillofacial area, the information regarding appropriate therapy for this tumor is limited. At present, adequate surgical excision appears to be the most appropriate procedure to prevent local recurrence. Treatment should focus on achieving negative margins and total extirpation of the tumor. The incidence of nodal metastasis is only 3%. SS is normally radioresistant in the extremities, but postoperative radiation therapy has been advocated for tumors in the head and neck region. Large doses in the range of 65 Gy or more are recommended.
Although the effectiveness of chemotherapy has not been proven, multidrug chemotherapy, such as adriamycin and ifosfamide, has been used in an attempt to prevent distant metastasis. Recently, some investigations reported that EGF receptor and HER-2/neu may play roles in the tumorigenesis of SS. Thus, antigrowth factor antibody therapies may provide a previously unrecognized therapeutic approach to these tumors. Post-treatment recurrence rate for SS arising from all body sites is approximately 50%. Most cases recur in the first 2 years after treatment. The 5- and 10-year survival rates in patients with SS in the head and neck were 46.7 and 32.7%, respectively. Prognosis is affected by tumor size, location, patient age, histological subtype, extent, mitotic activity and margin of resection. Tumor size is the most important prognostic factor. Patients with tumors of maximum diameter greater than 5 cm have a poorer prognosis. Despite advances in the treatment of local disease, distant metastasis remains the predominant cause of death.
Epithelioid sarcoma (ES) is a histologically distinct malignant STS of uncertain histogenesis. The origin of this rare neoplasm still remains controversial. ES is generally considered a high-grade STS, although grading is not currently recommended for this histological type. Some authors regard ES as a monophasic variant of SS. In some respects ES resembles SS, with a mixture of epithelial and spindle cell elements along with the presence of mucinous material in the surrounding ground substance. A recent analysis of the immunohistochemical pattern of both epithelial and mesenchymal markers led to the conclusion that ES is a mesenchymal tumor capable of partial epithelial transformation. It mainly occurs in young adults from 15-40 years of age and has a predilection for the fingers, hands, forearms and lower limbs. It is very rare on the trunk and head and neck regions. The clinical presentation is usually that of a slowly growing, painless swelling, which may be a solitary nodule or, more rarely, consists of multiple nodules and has firm consistency. The lesion may cause ulceration of the overlying skin or mucosa that fails to heal. Areas of calcification are occasionally seen in the lesion on radiographs. The tumor often presents difficulty with diagnosis, both clinically and histologically. This accounts for numerous misdiagnoses. Surgery is the treatment of choice. No significant survival difference was found between patients who received and who did not receive adjuvant chemotherapy or radiotherapy. Poor responsiveness to conventional chemotherapy has also been described.
Kaposi sarcoma (KS) is a spindle cell malignant vascular tumor thought to be of endothelial cell lineage. It is a slowly progressive, malignant mesenchymal tumor composed of proliferative connective tissue cells and capillary vessels. This initially rare neoplasm has become one of the most frequent vascular sarcomas due to its high prevalence in immunocompromised patients, mainly in those with AIDS. Currently, there is strong evidence that KS is caused by the human herpes virus VIII (HHV-8). KS-associated herpesvirus or HHV-8 is a member of Rhadinovirus genus, g-2 herpesvirus, known to infect humans, and recognized as an etiologic and diagnostic agent for KS and certain forms of malignant lymphoma. The mechanisms of primary oral mucosal HHV-8 infection and KS development remain elusive.
The observed higher viral load in oral KS compared with cutaneous KS is consistent with the previously documented importance of oral virus. Cases of KS associated with renal transplantation have also been reported. In the transplant setting, KS lesions have been shown to originate from the engraftment of donor tumor cells. Classic KS is still an infrequent neoplasm . It usually presents as indolent lesions affecting the extremities of older men, mainly of Ashkenazi Jewish or Mediterranean origin. Long-standing cases of classic KS may show visceral involvement that is frequently overlooked because it is usually asymptomatic and possesses a low malignancy potential. AIDS-related KS presents a completely different biologic behavior. It is much more frequent and more aggressive and usually affects young men. Histologically, KS lesions are composed of proliferating spindle-endothelial cells and admixed mononuclear inflammatory cells (lymphocytes, plasma cells and macrophages). Gene expression profiling confirmed that KS lesions do indeed consist of a mixture of endothelial cells and an inflammatory infiltrate. Regardless of the clinical form of KS, all cases show similar histologic features that are classified into three distinctive stages: the patch, plaque and nodular stages.
The occurrence of KS in oral tissues has been frequently reported as the first manifestation of AIDS. In this setting, oral KS is locally aggressive but rarely fatal and is characterized by multifocal lesions affecting the palate and tonsils. There are very few reports describing KS arising on the tongue of nonimmunocompromised patients. Less commonly involved sites are the buccal mucosa and lip. A similar pattern is thought to be seen with the classic form of KS. Many patients are asymptomatic when initially seen, but the lesions may ulcerate and become painful and bleed. Patients with classic KS of the oral cavity can be treated with primary excision, radiotherapy, intralesional chemotherapy or systemic chemotherapy. Primary excision can be performed with the use of the carbon dioxide or argon laser, both minimizing bleeding. KS is also known to be quite radiosensitive, typically requiring a total dose of less than 20 Gy. Usually superficial radiation beams, such as electron beams (400 cGy once weekly for 6-8 consecutive weeks), are used. Although systemic chemotherapy is often effective in the treatment of classic KS, it is not generally recommended in AIDS-related KS because it leads to further immunosuppression, which can affect survival. Current systemic therapy for KS includes liposomal anthracyclines (doxorubicin and daunorubicin) and paclitaxel. Although the response to paclitaxel was shown to be associated with a fall in plasma IL-6 levels, no change in other cytokines was noted, nor was there any significant change in CD4 cell count or HIV-1 viral load during chemotherapy. Localized injection of vinblastine has been performed for the treatment of both cutaneous and oral lesions. Because of its strong alkaline character, vinblastine is thought to act as a sclerosing agent, inducing fibrosis of the local site.
Malignant peripheral nerve sheath tumor
Some synonyms are neurogenic sarcoma, malignant schwannoma, neurofibrosarcoma, Triton’s tumor. Malignant peripheral nerve sheath tumor (MPNST) is a spindle cell sarcoma usually arising in proximity to peripheral nerves or shows nerve sheath differentiation. In 80% of the cases occurrence is in adults and in 20% in children and adolescents under the age of 20 years. The usual clinical presentation is that of an enlarging soft-tissue mass arising in the head and neck region with or without pain and dysesthesia. Most of the lesions are deep seated and may develop in a pre-existing neurofibroma. It is found in patients with Von Recklinghausen’ neurofibromatosis in 70% of cases. Because of the rarity of this tumor there are few published reports and little information is available on its clinical management. MPNST is reported to behave aggressively, with a high rate of local recurrence and distant metastasis. Favorable outcome seems to be associated with small and localized tumors that can be completely excised. The effectiveness of adjuvant treatment with either radiotherapy or chemotherapy is unknown. Despite these reports, using adjuvant chemotherapy with ifosfamide and doxorubicin regimen has been reported.
The finding of skeletal muscle fibers in MPNST of the sinonasal track has been associated with rhabdomyoblastic differentiation and these tumors are also known as malignant Triton tumor (MTT). The normal sinonasal soft tissues might occasionally contain a few ectopic skeletal muscle fibers that are inconspicuous unless searched for with immunohistochemistry. MTT denotes a malignant schwannoma with rhabdomyoblastic differentiation. One hypothesis is that malignant Schwann cells differentiate into rhabdomyoblasts. Another hypothesis is that both cell lines arise from less differentiated neural crest cells with both ectodermal and mesodermal potential. It was so named because it was thought that the malignant neural elements induced the differentiation of skeletal muscle in an analogous fashion to the production of supernumerary limbs containing bone and muscle by implantation of the cut end of a sciatic nerve, into the back of certain amphibians, notably the Triton salamander. MTT is a very rare diagnosis. Approximately 100 cases have been reported, several of them in the head and neck. Chromosomal abnormalities have been reported and probably play a role in the pathogenesis or in the progression of MTT. The patients are young, aged between 14 and 57 years, with an average age of 33 years. Histologically, the tumor cells exhibit strong immunoreactivity against antimuscle-specific actin, antimyoglobin, antineuron-specific enolase and antidesmin antibodies. The treatment of choice is complete surgical removal followed by radiation therapy and/or chemotherapy. Little is known concerning the radiosensitivity of MTT, and cytotoxic drug therapy has been characterized as of no value in its treatment .
Dermatofibrosarcoma protuberans (DFSP), an indolent, low-grade sarcoma recognized for its progressive, locally infiltrative nature, accounts for less than 5% of adult STSs and less than 1% of all malignant tumors of the head and neck. It typically presents as an asymptomatic indurated plaque or firm, cutaneous nodule in early-to-middle adult life. DFSP occurs most commonly in patients aged 20-50 years with no gender predilection. The anatomical distribution of tumors includes the scalp, face and neck. The lesions are typically fixed to the dermis but not to deeper lying tissue, and typically do not exhibit a nodular growth pattern until late in their course. The arrangement of spindle-shaped tumor cells in a ‘cartwheel’ or ‘whirligig’ pattern is a constant finding. This finding subsequently has been emphasized as diagnostically important and has been confirmed by other investigators as histologically specific for DFSP. The histogenesis of this tumor remains undefined. Classical DFSP is diagnosed when histological examination demonstrates a tumor arising in the dermis, consisting of irregular, interwoven fibrocellular fascicles composed of uniform spindle-shaped cells and variable amounts of collagen, which produce a storiform appearance. Regional nodal or distant metastases are exceedingly rare, and overall survival is excellent. Traditionally, DFSP has been treated with wide local excision and has had a 20% recurrence rate for all body sites. A higher recurrence rate (>50%) has been reported for the 15% of cases affecting the head and neck. DFSP of the head and neck is usually difficult to eradicate. The excision margins recommended for treating this tumor (2-3 cm) are insufficient to remove all histological evidence of tumor. The surgical method should be a 3D resection, which includes skin, subcutaneous tissue and the underlying investing fascia. Prognosis is excellent for DFSP after adequate surgical clearance. Overall 5-year survival rates are 93-100%. In several series, no patient has died of disease. Recently, improved tumor control has been reported for lesions treated by Mohs micrographic surgery (MMS), a procedure that many authors currently prefer for treating DFSP of the trunk and extremities. MMS has emerged as an alternative approach to the use of wide resection surgery with tumor-free margins. MMS is designed to treat tumors that involve extensive subclinical infiltration of the skin. MMS uses sequential horizontal sectioning with immediate microscopic examination of resected tissue by frozen section, a process that is repeated until a clear margin is obtained. The combination of conservative resection plus postoperative radiotherapy might be considered as an alternative for patients who cannot undergo wide surgical excision for medical, technical or cosmetic reasons. Recent advances in the understanding of the molecular pathogenesis of DFSP have led to the investigation of a new therapeutic approach that is based on targeted inhibition of the PDGF receptor (PDGFR) protein-tyrosine kinase. Most cases of DFSP feature a specific translocation of chromosomes 17 and 22 that results in constitutive production of PDGF B chain, autocrine activation of PDGFR and stimulation of DFSP growth. Targeted therapy with PDGFR resulted in favorable responses in patients with both locally advanced and metastatic disease. Treatment has generally been well tolerated, and the rate of relapse has been low.
Alveolar soft-parts sarcoma
Alveolar soft-parts sarcoma (ASPS) is one of the most unusual tumors of soft tissues and makes up only 0.5-1% of all STSs. Between 10 and 15% of cases are found in the head and neck. It most commonly arises in the skeletal muscles or musculofascial planes of the lower extremities in adults, and in the head and neck region in children, particularly within the orbit and the tongue. ASPS occur principally in adolescents and young adults (15-25 years of age). The biologic behavior of the tumor is deceptively indolent. ASPS presents in the head and neck region as a soft, painless, asymptomatic and slow-growing mass. It can produce local functional impairment, such as difficulty in speaking and dysphagia. Distant metastases may be found at the time of diagnosis, the lungs being the most common site. Metastatic spread is hematogenous and lymph node involvement is exceedingly rare. Microscopically, ASPS is characterized by large polyhedral cells separated by delicate vascular channels and bands of fine connective tissue that confer an organoid pseudoalveolar pattern to the tumor.
Histologically, the cells of ASPS are arranged in clusters with numerous vascular channels and thin connective tissue septa. The cells are in compact solid cell aggregates or in alveolar form with a central space devoid of organized structure. Several studies have been carried out using a variety of immunohistochemical stains, mainly to identify the cell of origin of the ASPS. Early investigators related ASPS to granular cell tumor and considered the Schwann cell as a possible origin. The immunohistochemical stains are usually reactive for vimentin, muscle-specific actin, desmin and cytoplasmic MyoD1. There is no consensus on the optimum treatment. Most authors agree that adequate surgical resection usually guarantees good local control and remains the cornerstone for therapy. Regional lymphadenectomy is not required unless nodes are clinically palpable. Adjuvant radiation therapy can be offered in cases with inadequate margins. The role of radiation in the treatment of patients with localized ASPS is difficult to define owing to the small number of cases in the literature. As complete excision of the primary tumor is rarely followed by local recurrence, the prognosis depends to a large extent on appropriate management of metastases, which are unpredictable and can be delayed up to three decades after primary diagnosis of the tumor. Metastatic ASPS is resistant to conventional doxorubicin-based chemotherapy and observation or novel therapies should be considered in patients with metastatic disease. The 10-year survival among cases without evidence of metastatic spread has been reported to be 38%, although 3- and 5-year survival rates of above 70 and 85%, respectively have been reported. Further studies addressing the use of systemic chemotherapy and its role in reducing distant metastasis are needed.
Malignant Tumors of Bone & Cartilage
Chondrosarcoma, including mesenchymal chondrosarcoma
A synonym is polyhistioma. Mesenchymal chondrosarcoma (MC) is a rare malignant tumor arising both within hard and soft tissues. Chondrosarcoma is a malignant tumor in which the tumor cells form chondroid (cartilage) but not osteoid. Although chondrosarcoma most commonly arises from either cartilaginous structures or bone derived from chondroid precursors, chondrosarcoma may also arise in areas where cartilage is not normally found. Involvement of the jaws is encountered in 22-27% of cases of MC. Maxillofacial MC has a propensity for recurrence and metastasis to lungs, bone and lymph nodes, sometimes occurring long after treatment, and is associated with an overall poor prognosis. The available gender information for all tumor sites indicates a female:male ratio of 1.6:1, whereas approximately two-thirds of patients with sinonasal tumors (64.6%) are women. The age of occurrence ranges between 30 and 70 years, with two-thirds of the patients in the fifth to the seventh decades of life. In the head and neck the tumor occurs most often in the maxilla followed, in order of frequency, by the body of the mandible, ramus, nasal septum and paranasal sinuses. It is possible that chondrosarcoma has a predilection for the maxilla because it often originates from the cartilaginous portions of the nasal structures or vestigial rests entrapped in them.
Most cranial-based chondrosarcomas develop from the cartilage of the sphenopetroclival synchondrosis. As a result they typically involve the cavernous sinus, the petrous bone, the sphenoid bone and the clivus. Patients usually have diplopia secondary to involvement of cranial nerves VI and III at presentation. Approximately 80% of adults with chondrosarcoma demonstrate an abnormal diabetic glucose tolerance curve. MC exhibits a bimorphic histologic pattern, with a highly undifferentiated small round cell component admixed with islands of well-differentiated cartilage. The histological features of MC are generally consistent, characterized by a biphasic pattern, with a sheet-like or patternless proliferation of small undifferentiated spindle or round cells surrounding discrete nodules of differentiated hyaline cartilage. Difficulty in classifying central cartilaginous tumors as benign or malignant occurs because relatively well-differentiated, hypocellular tumors can be malignant (i.e., low-grade chondrosarcomas). Conversely, tumors with worrisome features can be benign (i.e., chondromas with, e.g., pleomorphism, increased cellularity, myxoid features), thus making it virtually impossible to distinguish a low-grade chondrosarcoma from a chondroma.
Most systems developed for specifically grading chondrosarcoma use a three-tiered system. It is recognized that grade is a biologic continuum and, for that reason, any clear distinction between separate grades is arbitrary. As a result, it is reasonable to condense the specific four-grade system into a broader two-grade system defining a lower grade (as grades I and II) and a higher grade (grades III and IV). Array-CGH revealed significant correlations of c-Myconcogene amplification and polysomy 8 with enchondroma progression to dedifferentiated chondrosarcoma. Loss of chromosome 6 and gain of 12q12 were also identified by array-CGH as being associated with higher grade. Frequent fractional allelic losses in up to 66.7% of chondrosarcomas have been reported. Commonly, LOH was observed at 5q, 9p, 11p, 13q and 19q chromosomes. These genomic studies demonstrate the genetic heterogeneity of conventional MCs.
Wide surgical excision is the mainstay of treatment for MC in the jaw bones and for those arising in the skull base. Surgical clear margins are very important for favorable prognosis and for decreased risk of recurrence. Surgical treatment of recurrent disease is extremely difficult and most recurrent tumors have a dismay prognosis, death resulting from the direct extension of the tumor into vital structures. The overall low incidence of regional (5.6%) metastases may suggest that neck dissection is not indicated. Cranial-based chondrosarcomas are rare, but they present the surgeon with a unique challenge because wide local excision is impractical.
Chondrosarcomas are considered to be relatively resistant to radiation and opinions vary as to its value. Investigators have identified that chondrosarcoma is not a radioresponsive tumor and, as a result, radiotherapy is not useful as a primary modality nor as an adjunct to surgery. By contrast, other authors have noted acceptable outcomes with the use of radiotherapy.
Recurrent disease can be treated with further surgical resection or stereotactic radiation as needed, although recurrence is still associated with a worse prognosis. Because this disease is rare and has a low mortality rate, it is difficult to compare different treatment modalities to identify a single best approach. However, meticulous surgical resection together with postoperative radiotherapy provides the best long-term outcomes.
The use of chemotherapy with or without other therapy in most (57.5%) MC cases probably reflects efforts to expand treatment to address the advanced stage and grade of this histologic variant. Despite the recognized absence of statistical evidence supporting the value of adjuvant chemotherapy for chondrosarcoma, investigators have suggested it be considered for use in the management of high-grade cases. Chemotherapy regimens do not show an improved effect of combined therapy compared with surgery alone.
Histone acetylation and deacetylation play key roles in the regulation of chondrocytic differentiation, prompting investigation of the anti-tumor effects of histone deacetylase inhibitors. Apart from their potent inhibition of malignancy-related osteoclast-mediated bone resorption, anti-tumor activity of bisphosphonates has been demonstrated in chondrosaromas. Zoledronate inhibited cellular proliferation and induced nonapoptotic cell death in rat swarm chondrosarcoma cells, and inhibited rat swarm chondrosarcoma progression and significantly increased survival in a rat allograft model. Similarly, minodronate inhibited proliferation and invasive capacity in human chondrosarcoma cell lines and induced S-phase arrest and apoptosis. Consequently, bisphosphonates may be therapeutically valuable in the treatment of chondrosarcomas. Aggressive behavior of MC of the jaw, with a tendency for delayed recurrence and metastasis even many years after treatment, has been reported. All the recurrent cases also developed metastases. The most frequent site of metastases was the lungs (50%). Overall 5-year survival is 77.6% and disease-specific survival is 87.2%.
A synonym is osteogenic sarcoma. Osteosarcoma is a malignancy of mesenchymal cells that have the ability to produce osteoid or immature bone. The origin of these tumors is largely unknown. Osteosarcoma is the most common malignant primary bone tumor. Although it occurs at any age, its peak incidence is in the second and third decades. Its statistical distribution roughly parallels skeletal growth; it is more frequent in tall than in short people. Genetic predisposition, such as the Li-Fraumeni or Beckman-Wiederman syndrome, an underlying abnormality, such as Paget disease, or fibrous dysplasia that has a predilection for the development of osteosarcoma or previous radiation of the bone involved, may exist. The definition of osteosarcoma is deceptively straightforward. It is a malignant tumor of mesodermal origin within which the tumor cells produce bone or osteoid. Although this makes it seem as though the cells giving rise to osteosarcoma must be of osteoblastic derivation, there is no evidence that osteoblasts, once they differentiate from osteoprogenitor cells, can actually revert to more primitive cells, l et al. ne malignant ones. Although osteosarcoma usually arises in the medullary cavity of the metaphysis of a growing long tubular bone, it may also arise on the surface of a bone, it may be confined to the cortex or it may even arise in an extraskeletal site. The osteosarcomas arising on the bone surfaces are approximately 20-times less frequent than their medullary counterparts. Interestingly, the majority of osteosarcomas of medullary o-rigin are high grade, whereas most arising on the surfaces of bones are of lower grade. Patients with surface osteosarcomas are often a decade or more older than typical patients with central osteosarcomas.
As osteosarcomas may produce various kinds of extracellular matrix and have different degrees of differentiation, their histologic pattern may vary significantly, not only from case to case but also from area to area in the same case. Its classification into various subtypes is not only by the predominant histologic pattern, but also by its anatomic location and sometimes by its histologic grade.
Conventional osteosarcoma has been divided into osteoblastic, chondroblastic and fibroblastic subtypes depending on the predominant type of extracellular matrix. Approximately 10% of osteosarcomas occur in the head and neck and most are located in the mandible or the maxilla. Jaw lesions are diagnosed on average two decades later than their long bone counterparts, which have a peak incidence between the ages of 10 and 14 years. The most common signs and symptoms associated with osteosarcomas of the jaws consist of persistent pain, swelling and paresthesia/anesthesia. Radiographically, they are often radiolucent or a mixture of radiolucent and radiodense areas. The presence of the ‘classic’ sunburst or sunray appearance caused by osteophytic bone production on the surface of the lesion is present in 50% of the cases. The radiographic pattern of osteosarcomas of the jaws has been classified into lytic, sclerotic and mixed. No relationship was found between the radiographic pattern and the histologic type of osteosarcoma. Microscopic subclinical metastases are present at the time of diagnosis in the majority of patients.
Surgery remains the gold standard for the treatment of head and neck osteosarcomas. Resection with clear margins is the most important prognostic treatment factor. Goepfert et al. had no survivors in their series of 70 patients treated for osteosarcoma with positive surgical margins. Smeele et al. reported more favorable survival outcomes in patients without residual disease. Suggested margins are 2-3 cm in bone and soft tissue. Despite the extension of the surgical resection positive margins are found in at least 30% of the patients. Patients with clear surgical margins demonstrate better survival, fewer local recurrences and less metastatic disease.
Results of radiation therapy alone for the treatment of osteosarcoma are unacceptable. Use of radiation in the treatment of osteosarcoma in general is relegated to the treatment of positive margins after surgical resection or in cases of local, inoperable recurrences. Osteosarcomas are relatively radioresistant requiring more than 6000 cGy to be effective. Brachytherapy, which is used with some good results in the appendicular cases, has failed to show benefit in the head and neck. Although indications for adjuvant chemotherapy vary among institutions and even among clinicians within the same institution, there does appear to be a survival advantage in patients receiving chemotherapy. All protocols included the administration of ci-splatin, high-dose methotrexate and doxorubicin. Lately, ifosfamide and etoposide have also been used. Questions persist, however, regarding timing of chemotherapy, that is, neoadjuvant or after surgery. Neoadjuvant chemotherapy, although often applied in head and neck osteosarcoma, has not been conclusively established as being superior to prompt postoperative chemotherapy, at least in terms of survival benefit, but it does permit the potential advantages of early eradication of micrometastatic disease. Preoperative chemotherapy, however, offers several other advantages, such as gain of time in order to prepare definitive surgery for limb-salvage procedures and delineation of tumor, and contributes to the improvement of the quality and adequacy of the surgical margins. Osteosarcomas that are pretreated by chemotherapy are better demarcated against surrounding tissues as chemotherapy induces the development of a well-formed avascular, collagenous capsule making them easier to operate on. Neoadjuvant chemotherapy allows in vivo testing of the therapeutic regimen. Treatment response is considered successful if more than 90% of the tumor cells show necrosis histologically. However, histologic assessment of tumor necrosis during the course of chemotherapy requires repeated biopsies.
Extensive necrosis in the surgical specimen leads to postoperative cycles of chemotherapy using the same agents. Lack of significant necrosis results in substitution of other agents. Patients with osteosarcomas that do not express the p-glycoprotein (p170) multiple-drug-resistance gene have a vastly improved prognosis. It has been assumed that mutation of tumor suppressor genes participates in the development and progression of malignant tumors, including osteosarcoma, and it is anticipated that introduction of normal tumor suppressor genes into osteosarcoma cells may result in tumor growth inhibition. Gene therapy is one of the most promising strategies but few clinical trials of gene therapy for osteosarcoma have been carried out to date. Recent molecular genetic studies of osteosarcoma have shown that a significant proportion of osteosarcomas of all sites harbor alterations in the oncogenes p53 , mdm2 and Rb. Some osteosarcomas have a deletion of chromosome 13q14, the site of the Rb gene. The 5-year local control recurrence-free survival rates exceeds 75% and the overall survival 70%.
Extramedullary myeloid sarcoma
Some synonyms are granulocytic sarcoma (GS), extramedullary myeloid tumor, chloroma. GS is a localized infiltrate of immature granulocytes in an extramedullary site, which clinically resembles sarcoma. The characteristic green color of the tumor is due to the presence of myeloperoxidase (MPO) enzymes in the immature myeloid cells. GS is most frequently identified in patients known to suffer from acute or chronic leukemia or another myeloproliferative disorder. Clinically, GS can occur in three settings: in patients with previous or current acute myeloid leukemia (AML), as a sign of blast transformation in patients with chronic myeloid leukemia (CML) or other chronic myeloproliferative disorders, or in patients who were previously well. GS occurs at any age in the subperiosteal bone structure and soft tissue but can be found in any location throughout the body. Intraoral GS is rare, with only 30 reported cases, usually as a mass in the gingiva and palate or sites of extraction sockets.
Definitive diagnosis is only established following histological examination, including immunohistochemical analysis. The tumor mass comprises diffuse sheets of blast cells, which often show a single file pattern of infiltration in some areas. The blast cells have round or ovoid nuclei, very fine chromatin, small but distinct nucleoli and a small-to-moderate amount of lightly eosinophilic cytoplasm. The immunohistochemical analysis panel should include antimyeloperoxidase, CD68 (lysosome-associated antigen), CD43 and CD20. MPO can be identified by Sudan black B or by peroxidase or diaminobenzidine reactions. MPO is localized in the primary granules of the myeloid cells and is synthesized early in the differentiation and thus serves as an important marker for myeloid lineage. Abundant secretory granules in the tumor cells indicate the myeloblastic nature. This test allows us to distinguish between AML and acute lymphoblastic leukemia in which blast cells are negative for MPO.
Chemotherapy remains the mainstay of treatment of GS. The goal is to reduce the number of leukemic cells below clinical detection, thus achieving hematologic remission and restoring normal hemapoeisis. Radiation therapy (3600 cGy) is indicated. Gleevec ® , a selective BCR/ABL tyrosine kinase inhibitor, has demonstrated remarkable effectiveness and safety in the treatment of CML and is currently the first-line treatment for CML and might be useful in cases of GS. The prognosis for GS is poor, and comparable to that for adult acute leukemia.
Histiocytic sarcoma is a rare tumor that can occasionally present in the nasal cavity. It is defined as a malignant proliferation of cells showing morphologic and immunophenotypic features of mature tissue histiocytes. Histological diagnosis depends on the demonstration of histiocytic differentiation of myeloid markers. Histologic distinction from large cell lymphoma is difficult, except that the cytoplasm tends to be voluminous and eosinophilic. The frequent expression of CD43 may lead to a misdiagnosis of T-cell lymphoma. Treatment is similar with that of lymphomas.
Follicular dendritic cell sarcoma
Follicular dendritic cell (FDC) sarcoma (FDCS) derives from immune accessory cells of the peripheral lymphoid tissue. FDCSs are uncommon and the majority of them involve lymph nodes with a few cases in extranodal sites. Dendritic cells are a heterogeneous group of immune accessory cells present in lymphoid and nonlymphoid organs that share a common ultrastructural appearance of cytoplasmic dendritic processes. FDCs are localized in the germinal centers of lymphoid follicles and participate in the immune system by presenting and retaining antigens for B cells and stimulating B proliferation and differentiation. In addition, FDCs are known to have complex interaction with T cells. Indeterminate cells have been interpreted as pre-Langerhans cells that have not acquired Birbeck granules and whose exact function is still unknown.
Langerhans cells are dendritic cells localized in epithelial tissues containing the distinctive Birbeck granules. The Langerhans cells carry surface receptors for immunoglobulin and complement, and are believed to have an immunologic function, recognizing and processing antigen material that crosses the epithelium barrier from the external environmental and presenting it to T-helper lymphocytes. Extranodal tumors from this group are extremely rare. In the oral cavity only eight cases of FDCSs have been reported. The etiologic factors associated with FDCS are unknown, but a small proportion of nodal cases appear to be associated with the hyaline vascular type of Castleman’s disease and a very few, mainly those located in the liver, have been associated with Epstein-Barr virus infection. FDCSs are identified immunohistochemically by their reactivity with CD21, CD35, R4/23 and Ki-M4. The data in the reports suggest that the lesion occurs most commonly in young-to-middle-aged adults as a mass noticed from a few weeks to a few years before presentation. In each patient with involvement of the oral cavity, the tumor has manifested itself as a mass without clinical evidence of lymph node involvement. The optimal treatment for this tumor remains uncertain. The great majority of patients have been treated surgically, often followed by radiotherapy or adjuvant chemotherapy, but such supplemental treatments have not been proven to contribute to long-term survival. Local recurrences occur at a median of 15 months. FDCS has a recurrence rate of more than 43%, with metastases documented in more than 24% of cases.
A synonym is peripheral primitive neuroectodermal tumor. Ewing sarcoma (EWS), a highly malignant tumor, is the second most common bone tumor in children and adolescents. It constitutes approximately 6% of malignant bone tumors. Although it has been reported as occurring at all ages, by far the majority develop within the first two decades of life. In the second decade, it is the most common primary neoplasm of bone after osteosarcoma. The usual site of occurrence is in the diaphysis of long bones, less often in ribs, pelvis and vertebrae. The location of the primary tumor in the head and neck occurs in approximately 2% of cases. Rarely it develops in the jaws and in those cases affects the mandible three times more than the maxilla. EWS located in the middle third of the face shows some characteristics distinctive from those that are normally described in other regions of the body. The most common manifestations are related to the effect of the tumor mass. The signs and symptoms in this location are usually the appearance of a palpable mass on one side of the face, sometimes accompanied by pain, inflammation in the maxillary sinuses and orbital invasion. Radiographic findings are nonspecific. The lesion may produce a diffuse irregular radiolucency with ill-defined margins. The most characteristic radiographic appearance is that of a motheaten destructive radiolucency with or without erosion and cortical destruction or expansion. A variable periosteal ‘onion-skin’ reaction may also be seen, as may a ‘sun-ray’ appearance.
Chromosomal instability has been confirmed by several studies. The characteristic translocations involve the EWS gene at 22q12 and either the FLI1 gene at 11q24 or the ERG gene at 21q22. Recent investigations suggest that different types of EWS-FLI1 fusions (type 1 vs type 2) may have prognostic implications. Patients with type 1 fusions (in which EWS exons 1-7 link with FLI1 exons 6-9) do better than patients with type 2 fusions. This relationship remains under investigation. Additionally, ES/PNET expresses elevated levels of a 32-kDa cell surface glycoprotein p30-32, known as cluster of differentiation 99 (CD99), a mic2 gene product. Histologically the typical case of EWS shows a lobular growth pattern of tumor cells that are distinctly monotonous in their nuclear uniformity. Nuclei measure 10-15 mm in diameter with distinct nuclear membranes.
Large areas of perivascular tumor necrosis with ‘ghost cells’ (filigree pattern) may be striking. Areas of neuroectodermal differentiation (Homer Wright rosettes; rarely Flexner-Wintersteiner rosettes or primitive neuroepithelium) may be evident in some tumors. For many years, EWS was essentially an immunohistochemical diagnosis of exclusion. More recently, numerous data have been published regarding the expression of the mic-2 gene product (HBA71 antigen or CD99) in this group of tumors confirming the high sensitivity of this marker for EWS family tumors detected via 12 E7, HBA 71 or O13 antibodies. The mic-2 gene is a pseudoautosomal gene located on the short arm of the sex chromosomes, and its product is a membranous glycoprotein that can be detected immunohistochemically. Its function has a role in cellular adhesion and regulation of cell proliferation. Immunostaining for CD99 ( mic-2 ) is highly sensitive for EWS and has been shown to be expressed in well over 90% of EWS tumors with a characteristic membranous pattern.
Traditional treatment of EWS has included surgery and local irradiation. When surgical resection is impossible, or in cases in which surgery is performed but margins are microscopically positive or ‘close’, radiation therapy to cumulative doses of between 45 and 55.8 Gy can control most cases. Recent studies have reported that the combination of chemotherapy and radiotherapy has dramatically improved the long-term survival rates of patients with EWS with cure rates approximately 50-60%. The use of adjuvant chemotherapy since the early 1970s with vincristine, cyclophosphamide and dactinomycin improved patient survival and the addition of doxorubicin and ifosfamide with or without etoposide during the recent years produced remarkable responses in patients who have had a relapse after standard therapies. This improvement appeared to be greatest among patients with large primary tumors, although older age remained an adverse prognostic factor. Neoadjuvant chemotherapy is followed by either surgical excision or radiation therapy, depending on tumor response to medical treatment. However, despite these aggressive treatments, approximately 30% of patients with localized disease at diagnosis still develop metastases and/or local recurrence and died of their disease. It seems possible that patients with metastases at presentation, who had never received chemotherapy before diagnosis, might be more sensitive to systemic treatment in comparison with patients who relapse after an aggressive adjuvant chemotherapy.
Intensive chemotherapy with stem cell rescue seems to have a role in the treatment of EWS patients with high risk of metastases at presentation. Treatment with total body irradiation followed by autologous bone marrow transplantation has also been used with promising results.
The overexpression of VEGF in EWS samples was recently studied. Angiogenesis, the neovascularization or formation of new capillaries from pre-existing vessels, is a rate-limiting factor for the growth and expansion of tumors. Several features of the microenvironment regulate the formation of the vasculature, including angiogenic factors such as VEGF, bFGF and PDGF, and influences hypoxia, necrosis and metabolic rate of the tumor. Survival analyses revealed that VEGF overexpression is strongly correlated with poor survival. Cyclin D1 is a critical regulator of progression through the G1 phase of the cell cycle, and its overexpression is implicated in the development of several cancers. The oncoprotein HER2/Neu belongs to the family of receptor tyrosine kinases, is over-expressed in several cancers and has become an attractive target for pharmacological intervention. VEGF protein is overexpressed in 55% of EWS specimens. Inhibition of angiogenesis, by targeting the comparatively homogenous and genetically stable endothelium, represents a promising approach to cancer therapy. There are currently more than 75 agents that target tumor vasculature either directly or indirectly in clinical trials, including 12 that have entered or completed Phase III trials. Unlike the more conventional chemotherapeutic approaches, little or no acquired drug resistance has been reported following treatment with inhibitors of angiogenesis. Treatment with Flk-1/KDR receptor tyrosine kinase inhibitors and anti-VEGF agents strongly supports the further evaluation of antiangiogenic agents for the development of new therapeutic strategies in EWS.
Some synonyms are ameloblastic sarcoma, ameloblastic fibrodentino sarcoma, fibro-odontosarcoma, ameloblastic dentinosarcoma, ameloblastic odontosarcoma, odontogenic sarcoma. Ameloblastic fibrosarcoma (AFS) is a very rare odontogenic tumor and can be considered the malignant counterpart of the ameloblastic fibroma. AFS is characterized by a biphasic pattern. Epithelial and mesenchymal components without enamel or dentine components form the lesion. Furthermore, the mesenchymal component is malignant. A total of 30 cases of AFS are reported in the literature. The average age at presentation for reported cases is 26.8 years. A total of 71% of patients with AFS were under the age of 20 years. It appears more often in the mandible than in the maxilla, and in men rather than women. AFS has been documented as arising in the jaws either de novo or from a pre-existing benign odontogenic neoplasm. The finding that AFS occurs at a later age compared with its benign counterparts has been used to support a theory of stepwise malignant transformation of a benign to a malignant tumor, as opposed to de novo malignancy. There are many reports of ameloblastic fibroma transforming into AFS after aggressive surgical treatment. Histologically AFS shows hypercellularity of the mesenchymal component with patchy distribution of hypercellular and hypocellular areas. The cells are pleomorphic with hyperchromatic nuclei, and occasionally malignant multinucleated giant cells are detected. The arrangement of the cells in bundles simulating the herring bone pattern, cartwheel or storiform pattern, occasionally extracellular pink material in a lace-like disposition are identified. Until recently, immunohistochemical stain was of limited value in the diagnosis of AFS because of the rarity of cases and the relative lack of immunohistochemical data in the previous reports.
Recent molecular analysis restricted high expression of the c-KIT gene in the sarcomatous component of the tumor. The c-KIT gene, located in chromosome 4, is a proto-oncogene that transcribes a transmembrane receptor with tyrosine-kinase activity for stem cell factor. Mutations in both the regulatory regions and the kinase domain lead to overexpression and activation of this oncogene. Despite the clearly malignant histologic features of the AFS, metastases rarely occur. Due to their rarity optimization of treatment is difficult and the limited number of cases reduces the reliability of retrospective analysis. Based on case report data, the optimum treatment is surgical resection with wide surgical margins. High local failure rates in patients who underwent a more conservative surgical approach are reported. Adjuvant therapy in the form of radiation or chemotherapy is reported in only a handful of cases with no conclusive evidence.
Approximately 60% of all patients with cancer will receive radiation therapy at some point in the course of their disease, either primarily for cure or for palliation. While radiation therapy is generally effective in the treatment of malignant tumors, it also has the potential to induce malignant change. Direct radiation effects on normal tissue may be lethal or sublethal. Lethal damage is caused by ionization within the DNA, preventing cell replication and resulting in tissue death. Sublethal damage may cause cell mutation leading to further neoplasia. Additionally, radiation reduces the proliferation of bone marrow, periosteal and endothelial cells and the production of the extracellular matrix and, in particular, collagen. Ionizing radiation is known as having a mutagenic potential. The p53 gene is a well-known tumor suppressor gene that has a pivotal role in regulating cell cycle, genomic stability, differentiation and apoptosis. Overexpression of mutant p53 represents the most common genetic change in oral squamous cell carcinoma and the aberrant p53 immunoreactivity is correlated with oral tumorigenesis.
p53 mutations in the process of radiation-induced malignant transformation have also been reported. Sarcoma arising in sites of previous radiation is a well-described entity. The diagnostic criteria for RIS include: RIS should arise in the area subjected to the irradiation, a latent period of some years has elapsed since radiotherapy and must be diagnosed histologically as a sarcoma. The radiation dose is usually no less than 2000 cGy. The latent period for the development of RIS can range from 3 to 30 years. Most sarcomas have been reported to occur after exposure to 5500 cGy with the dose ranging from 1600 to 11200 cGy. Although a minimum dose of 1000 cGy appears to be necessary, doses less than 3000 cGy are unlikely to result in sarcomatous transformation. Radiation can induce tumors in nearly any tissue or organ but, in general, the most common radiation-induced malignancies are leukemias and bone sarcomas. Ionizing radiation has been recognized as a carcinogen ever since Roentgens discovered x-rays in 1895. In the following years, many irradiation therapy-related secondary tumors, mostly sarcomas in the body and extremities, have been reported. Fibrosarcomas of the tongue following radium implants were reported in the 1920s and 1930s. Most of these early reports, however, suffer from a lack of convincing histological evidence apart from the fact that the histological classification of sarcomas has undergone numerous and drastic changes in recent times. Recently, radiation-induced malignancies of the head and neck in the sinuses, pharynx, thyroid, esophagus and skin have been reported in many studies. The incidence of sarcoma after radiation therapy ranges from 0.03 to 0.80%. In the head and neck region, the incidence of radiation-induced secondary cancers (including carcinoma and sarcoma) was reported to be 0.70%. RIS of the head and neck region include osteosarcoma, fibrosarcoma, condrosarcoma and MFH. MFH has been the most common defining type of RIS. RISs have a bimodal pattern of age distribution. The highest incidence of RIS is for ages 10-19 years and a second peak occurs after the age of 50. This is in contrast to the age distribution of patients with spontaneously occurring sarcoma that more frequently occurs in the third or fourth decade of life. The early peak of RIS is probably due to survivors of childhood neoplasms, and the second peak is due to survivors of all other solid tumors treated with radiation therapy. Although the incidence of RIS is rare, its biological behavior is more aggressive than spontaneous tumors. Originally, it was thought ionizing radiation-induced mutation was the sole cause of second primary tumors. However, studies suggest that ionizing radiation is not the cause of second primary cancers, but rather poses an increased risk of site-specific (field of radiation) carcinogenesis in the genetically susceptible population. Successful treatment of RIS is difficult, especially for high-grade lesions. The prognosis of RIS is generally thought to be worse than primary sarcomas, regardless of site. Several factors account for this. Commonly, there is a delay in diagnosis until an advanced stage of disease because of the frequently difficult distinction between neoplastic and radiation changes. Secondly, a high-grade histology is more frequently encountered, which may make these tumors inherently more aggressive. Finally, immunosuppression due to the primary cancer and/or its treatment may further worsen prognosis.
Expert commentary on treatment
The mainstay of treatment of sarcomas of the head and neck is still surgical extirpation. Radical resection to achieve wide negative margins in the head and neck is especially difficult because of inherent anatomic limitations and resulting cosmetic or functional sequelae. Because STSs expand spherically and along tissue planes, their centrifugal growth creates a false capsule, or pseudocapsule, of pressed surrounding tissue. Malignant cells penetrate this pseudocapsule. Simple removal of visible tumor in this plane leaves microscopic disease behind, and 90% of tumors recur unless there is further treatment. Over 30% will recur even after further excision of the tumor bed, and the subsequent use of radiotherapy does not compensate for the presence of unplanned positive histologic margins. Approximately a third of patients with a lower intermediate-grade tumor and wide resection margins will not require further treatment. Radiotherapy has little role in primary low-grade soft-tissue and bone sarcomas, although it should be considered for a recurrence. Almost all major series have reported equivalent control rates for surgery and surgery with postoperative radiotherapy. Radiotherapy is delivered as either external beam therapy or brachytherapy. Brachytherapy has theoretical advantages postoperatively, as local doses are high, but the dose decreases proportionally with increasing distance from the tumor bed. The aim of chemotherapy is the systemic control of both residual tumor and micrometastases and may be therapeutic, adjuvant or palliative. Although some subtypes of soft-tissue and bone sarcomas are sensitive to chemotherapeutic agents, the outcome of therapeutic chemotherapy is unsatisfactory overall, and the use of adjuvant chemotherapy is controversial. Adjuvant chemotherapy decreases the incidence of local recurrences but has no significant influence on the rate of distant metastases and does not extend overall survival.
Therefore, chemotherapy has been used as an adjuvant treatment hoping to improve local control and survival. However, randomized trials regarding the use of chemotherapy has not shown so far any specific benefit in survival or local control in adult head and neck sarcomas. In 1995 a meta-analysis of 14 trials testing doxorubicin-based postoperative chemotherapy found that it significantly reduced local failures and distant metastases, and improved disease-free survival. Intensified treatments of neoadjuvant chemotherapy with split-course radiation therapy followed by surgical resection and postoperative adjuvant chemotherapy improved the actuarial 5-year local control disease-free survival rate and overall survival from 45 to 84% and from 60 to 93%, respectively. The study showed that an aggressive neoadjuvant regimen can generate efficacy outcomes despite the substantial toxicity of the treatment. Intensified chemotherapeutic protocols remain moderately active against unresectable sarcomas in the pediatric population, but in patients with metastatic disease continue to have little or no effect. In two recent studies a new chemotherapeutic agent ecteinascidin (ET-743) was tested in patients with pretreated advanced STS. Ecteinascidin (ET-743) is a novel tetrahydroisoquinoline compound isolated from the marine ascidian Ecteinascidia turbinata. ET-743 is a unique DNA-interacting agent with covalent binding to the DNA minor groove. ET-743 blocks cell cycle progression in G2/M phase through a p-53 -independent apoptotic process and inhibits the transcriptional activation of inducible genes. In addition, ET-743 has shown important preclinical activity against a number of human solid tumor cell lines and xenografts, including sarcomas, with minimal or no cross-resistance to several conventional chemotherapeutic agents. Although ET-743 showed limited pharmacologic efficacy in this cohort of patients, it could become a relevant therapeutic option in patients with anthracycline/ifosfamide-resistant sarcomas in the future.
Encouraging progress is occurring with the use of therapies directed against specific molecular targets associated with head and neck sarcomas. Several protein tyrosine kinase inhibitors are under evaluation and prospective controlled trials will probably establish them as the treatment of choice for advanced inoperable or metastatic sarcomas. Angiogenesis is a potential therapeutic target. Several types of head and neck sarcomas express VEGF. The efficacy of a VEGF, neutralizing antibody in other tumors, posits the use of the antiangiogenic process in the definitive treatment of head and neck sarcomas.
Surgery will remain the mainstream of therapeutic approach for head and neck sarcomas. Novel radiotherapeutic techniques, such as intensity-modulated radiation therapy, hyperfractionation and radiosurgery, will allow maximal doses necessary for the tumoricidal effectiveness of treatment for these generally radioresistant tumors. The evolution of molecular studies and the recognition of new oncogenes will produce new generations of targeted therapies. These targeted therapies, and especially the antiangiogenic factors, will greatly improve management of locoregional recurrences and distant metastases, along with classic adjuvant chemotherapy.