General Principles and Management



General Principles and Management


Brian O’Sullivan

Abha Gupta

Patrick Gullane



INTRODUCTION

Sarcomas are rare malignancies of mesodermal origin. The annual incidence is <10,000 per year in North America. Fifteen percent of cases occur in the head and neck region comprising <1% of all head and neck cancers. Not only are they rare, but also an excess of 40 histopathologic subtypes may affect numerous anatomic sites within the head and neck. Unique challenges present themselves in the head and neck demanding special expertise in nutritional support, dental and voice rehabilitation, ophthalmology, and social support.1 The rarity and complex nature of these tumors warrant referral to specialized centers for multidisciplinary evaluation, including expert imaging and pathology assessment.2 All such consultations and evaluations should take place prior to therapy. A recent report evaluated outcome in 4,205 operative cases of soft tissue sarcomas (STS) and showed that high volume centers (those in the upper one-third of case volume in a geographic region) had better survival outcomes in numerous sites, including the head and neck, which comprised 12% of the cases studied.3 Smaller centers may have more difficulty formulating a multidisciplinary team with all necessary components of care, including access to an effective multidisciplinary cancer conference that meets frequently and regularly. This is especially so for head and neck sarcoma management where the case volume is low. It may be preferable to have linkage with the main sarcoma team at the center so that treatment protocols and pathology expertise are maintained as consistently as possible. We have found the latter approach to be essential in our practice even though both the overall sarcoma referral and the head and neck program are of substantial size.

The management of head and neck sarcoma follows principles extrapolated from other anatomic sites where the disease is more common.4,5 Although primary data about the head and neck would be desirable, evidence that the biologic behavior differs by anatomic site is not apparent. What sets these lesions apart from tumors elsewhere are the unique functional and cosmetic imperatives of the treatment.1 Thus, both surgery and radiotherapy must be applied more precisely and with greater complexity than elsewhere in the body because of the presence of critical anatomy. In particular, juxtaposed neurologic tissues (especially optic apparatus, spinal cord, and brain stem), nonexpendable vascular anatomy, organs necessary for speech and swallowing, and cosmetically sensitive tissues provide substantial challenges.

The chapter provides general information for both soft tissue tumors and their osseous counterparts relying on individual center experience, outcome reports from several registries, and reports of meta-analyses and clinical trials where these are available. Management focuses on the principles of curative approach initially for the more common STS, followed by bone tumors. The discussion of adjuvant systemic treatments will rely for the most part on published meta-analyses for soft tissue sarcoma and the meta-analysis (overviews) that have been undertaken in head and neck osteosarcoma. Special features in the head and neck including treatment or behavior of unique histologic subtypes are also acknowledged. The general problem of salvage for recurrence and the treatment of metastases (soft tissue and bone) will conclude the discussion.


PATHOLOGY AND GRADING

Soft tissue and bone sarcoma may present in a nondescript manner related to the presence of a mass, since the full range of histologic subtypes seen in other body sites can present in the head and neck. However, there are also several rare clinical entities that are disproportionately represented in the head and neck but space limitations prevents a comprehensive discussion. A summary of some of the main issues to be considered in evaluating and classifying these lesions is presented. A brief description of particular clinical features different histologic subtypes is also presented later.



Classification of STS Subtypes

The most common classification scheme for soft tissue sarcoma is based on histogenesis, as outlined in the World Health Organization (WHO) classification (Table 29.1).6 The classification is reproducible for the better differentiated tumors. However, as the degree of histologic differentiation declines, the determination of cellular origin becomes increasingly difficult. In the head and neck, as elsewhere in the body, the prototypical STS has been the malignant fibrous histiocytoma (MFH) but additional unique predispositions include nonpleomorphic rhabdomyosarcoma, angiosarcoma of the scalp and facial regions, hemangiopericytoma of the sinonasal region (Fig. 29-1), and dermatofibrosarcoma protuberans of the dermal regions of the low neck and supraclavicular regions. Recently, advances in molecular genetic pathology are influencing the classification, diagnosis, and treatment of soft tissue tumors of the head and neck.7,8,9 Molecular biologic techniques are becoming the preferred means of understanding the pathogenesis and behavior of sarcomas, and the specific chromosomal aberrations found in certain types of sarcoma can be exploited for diagnosis. Already a number of cytogenetic findings and corresponding genetic abnormalities characterize a number of the histologic subtypes (Table 29.2). For example, in synovial sarcoma, the t(X;18) translocation can almost invariably be detected with the demonstration of a fusion between the SSX and SYT genes providing a very useful diagnostic tool that is also associated with the two morphologic forms of this disease (the SSX1 associated with monophasic histology and the SSX2 gene with biphasic histology) (Fig. 29-2). The specific molecular subtypes of the SYT-SSX fusion transcripts have also been associated with prognostic discrimination,10 although this evidence has recently been overshadowed by observations that morphologically determined tumor grade may override this.11








TABLE 29.1 Principal Histologic Types of Soft Tissue Sarcoma in the World Health Organization (WHO) Classification of Bone Tumors with International Classification of Diseases for Oncology (ICD-O) Morphology Rubrics Listed in Alphabetic Order






























































Histologic Type


ICD-0 Morphology


Alveolar soft part sarcoma


9,581/3


Angiosarcoma


9,120/3


Clear cell sarcoma


9,044/3


Dermatofibrosarcoma protuberans


8,832/3


Epithelioid sarcoma


8,804/3


Extraskeletal chondrosarcoma


9,220/3


Extraskeletal osteosarcoma


9,180/3


Fibrosarcoma


8,810/3


Leiomyosarcoma


8,890/3


Liposarcoma


8,850/3


Malignant fibrous histiocytoma


8,830/3


Malignant hemangiopericytoma


9,150/3


Malignant mesenchymoma


8,990/3


Malignant peripheral nerve sheath tumor


9,540/3


Malignant Schwannoma, melanotic


9,560/3


Rhabdomyosarcoma


8,900/3


Synovial sarcoma


9,040/3


Sarcoma NOS (not otherwise specified)


8,800/3


Source: From Weiss SW, Sobin LH. Histologic Typing of Soft Tissue Tumors. 2nd ed. Berlin, Germany: Springer-Verlag; 1994, with permission.


Nonpleomorphic rhabdomyosarcoma, most often of alveolar histology, can be defined by the presence of PAX3 or PAX7 translocation, partnered with FOXO1, which is much more sensitive at defining the biologic behavior than histology alone.

Since the late 1970s, MFH has borne the mantle of most common STS of middle and late adulthood and is therefore mentioned specifically though it has no particular predilection for head and neck and there is now doubt about its status as a specific entity. Originally described in the 1960s, the term MFH was used to describe a group of sarcomas considered to have a mixed histiocytic and fibroblastic lineage. However, it is now regarded as a heterogeneous group of tumors without a specific line of differentiation. Reclassification of many tumors in this group seems to afford better prognostication and the old term “MFH” is generally considered obsolete today.12 Current nomenclature recognizes the entities undifferentiated high-grade pleomorphic sarcoma (previously storiform-pleomorphic “MFH”) and myxofibrosarcoma (formerly myxoid “MFH”).







FIGURE 29-1. Hemangiopericytoma of the left nasal fossa in a 40-year-old. This patient underwent resection with positive margins for well circumscribed lesion in 1994 (A and B). Postoperative radiotherapy to a dose of 60 Gy achieved durable local control. After 8 years, he relapsed with two bone lesions one in the left chest wall and the second in the right pelvis without other lesions shown on nuclide bone scan (C). Both lesions were successfully treated with combined radiotherapy and surgery but diffuse metastases resulted several years later. The original primary site also shows nucleotide uptake but cross-sectional anatomic imaging and clinical examination failed to reveal recurrent tumor.









TABLE 29.2 Cytogenetic Abnormalities in Soft Tissue Sarcoma



























































Histologic Subtype


Usual Translocations


Genes Involved


Alveolar sarcoma of soft parts


t(X;17)



Chondrosarcomas extraskeletal myxoid


t(9;22), (q22;q12.2)


EWS/CHN


Clear cell sarcoma


t(12;22)(q13;q12)


EWS/ATF1


Congenital infantile fibrosarcoma


t(15;15)(p13;q25)


ETV6, NTRK3


Dermatofibrosarcoma protuberans


t(17;22)(q22;q13)


Collagen type 1 α1; PDGF-B


Desmoplastic small round-cell tumor


t(11;22)(p13;q12)


EWS/WT1


Lipoma (minimal atypia)


12q abnormalities


Amplified 12q 13-15


Liposarcoma (myxoid)


t(12;16)(q13;p11)


TLS/CHOP



(12;22)(q13;p12)


CHOP/EWS


Liposarcoma well differentiated


Rings and giant markers


Amplified 12q13-15; HMG1-C CDK4; MDM2


Rhabdomyosarcoma (alveolar)


t(2;13)(q35;q14) t(1;13)(p36;q14)


PAX3 (or 7)/FKHR


Rhabdomyosarcoma (embryonal)


Loss of heterozygosity at 11 p15



Synovial sarcoma


t(X;18)(p11.2;q11.2)


SYT/SSX1 or SSX2



Grading STS

One of the most durable prognostic factors for the risk of distant metastasis and tumor-specific mortality in STS is histologic grade whose effect is so pronounced that it is included in the staging classification. Although a number of grading systems have been used in the management of soft tissue sarcoma, the three-tier system proposed by the French Federation of Cancer Centres is precisely defined, easy to use, and most widely employed. The French system relies on a relatively balanced evaluation of
parameters (differentiation score, mitoses, necrosis), but its greatest limitation lies in the assignment of a differentiation score.13 Roughly defined as the extent to which a lesion resembles normal tissue, differentiation score has little applicability for tumors which ostensibly have no normal tissue counterpart.






FIGURE 29-2. A: Coronal projection of computed tomography (CT) of an 18-year-old patient with synovial sarcoma arising from the left temporomandibular joint region. There is a large heterogeneously enhancing soft tissue mass causing distortion of the facial contour. Remodeling of bone is apparent as well as spiculated periosteal reaction and calcification. The diagnosis was established by the characteristic molecular gene fusion and translocation seen in synovial sarcoma (see text). B: T1 sequence postgadolinium magnetic resonance image (MRI) in coronal plane of the patient in A. The expansile mass is again apparent with heterogeneous features centered along the mandibular ramus and involving the temporalis muscle into the suprazygomatic masticator space.

It is also recognized that no system performs perfectly in all sarcomas. In a recent review, Deyrup and Weiss highlighted problems including the fact that some STS do not lend themselves well to grading. These include (a) those in which grade provides no additional information (e.g., well-differentiated liposarcoma/atypical lipomatous neoplasm); (b) “ungradable” histologic subtypes (e.g., epithelioid sarcoma, clear cell sarcoma, angiosarcoma); and (c) sarcomas that have traditionally been graded but where this characteristic does not appear to differentiate these lesions prognostically (e.g., malignant peripheral nerve sheath tumor [MPNST]).13


CLASSIFICATION OF SELECTED BONE SUBTYPES

In contrast to STS, primary malignant tumors of bone are predominantly confined to two histologic types: osteosarcoma and chondrosarcoma. Other histologies including primitive neuroectodermal tumor/Ewing sarcoma are much less frequent in the head and neck although a wide variety of histologic subtypes may be found14 (Table 29.3).


Osteosarcoma

Osteosarcoma is a primary malignancy of osteoblastic tissue and is discriminated from all other tumors, including chondrosarcoma, by the direct formation of bone or osteoid tissue by its tumor cells. It covers a wide spectrum of lesions with distinct clinical and pathologic features. The malignant component comprises an undifferentiated stroma characterized by dense cellularity, pleomorphism, and cytologically atypical osteoblasts. Although the tumor is derived from osteoblasts and the malignant cells can be shown to contain intracytoplasmic alkaline phosphatase, it usually exhibits a mixed picture containing fibroblastic, osteoblastic, and chondroblastic areas, based on the predominant characteristic of the stroma. Tumor osteoid may be seen copiously with numerous pleomorphic tumor osteoblasts.

Smith et al. reported the largest series, that of the National Cancer Data Base (NCDB), for patients diagnosed with osteosarcoma of the head and neck from 1985 to 1996.15 Accounting for about 5% to 10% of all osteosarcomas, they most usually affect individuals in the fourth decade of life of equal gender. The mandible (40%) and maxilla are the most frequent bones involved, although other skull bones may be affected.15 In general, it is perceived that they often comprise low-grade lesions, different from their high-grade counterparts found in the long bones, have a lower potential for metastatic spread compared with other sites, and thus patients with these tumor may not necessarily benefit from neoadjuvant or adjuvant chemotherapy.


Chondrosarcoma

Chondrosarcoma constitutes approximately 10% of malignancies of bone and is the second most common sarcoma of bone after osteosarcoma. Like osteosarcoma, the largest series (n = 400) of chondrosarcoma of the head and neck was also reported from the National Cancer Data Base (NCDB) for the years 1985 to 1995.16 This comprised 0.1% of head and neck cancers during the same period and makes up 1% to 12 % of chondrosarcoma in various reports.16 The hallmark of chondrosarcoma is its origin from tumor cells that form chondroid (cartilage) as opposed to osteoid. In addition, most (60%) arose from osseous tissue grouped as “head and neck bones” and “sinonasal,” the latter including 8% originating in the mandible. Almost one-quarter
arose from the laryngotracheal cartilages.16 While a rare site for chondrosarcoma, the cricoid lamina of the larynx is a unique tumor of generally indolent behavior.








TABLE 29.3 Principal Histologic Types of Bone Sarcoma Selected from the Second Edition (1993) World Health Organization (WHO) Classification of Bone Tumors



































































































Histologic Type


ICD-0 Morphology


Bone-forming tumors


Conventional central osteosarcoma


9,180/3


Telangiectatic osteosarcoma


9,183/3


Intraosseous well-differentiated (low-grade) osteosarcoma


9,180/31


Round-cell osteosarcoma


9,185/3


Parosteal (juxtacortical) osteosarcoma


9,190/31


Periosteal osteosarcoma


9,190/32


High-grade surface osteosarcoma


9,190/33


Cartilage-forming tumors


9,220/3


Chondrosarcoma


9,220/3


Juxtacortical (periosteal) chondrosarcoma


9,211/3


Mesenchymal chondrosarcoma


9,240/3


Dedifferentiated chondrosarcoma



Clear cell chondrosarcoma



Malignant chondroblastoma



Marrow tumors (round-cell tumors)


9,150/3


Ewing sarcoma


9,260/3


Primitive neuroectodermal tumor of bone


9,473/3


Malignant lymphoma of bone


9,590/3


Myeloma


9,732/3


Vascular tumors



Angiosarcoma of bone


9,120/3


Malignant hemangiopericytoma


9,150/3


Other connective tumors


9,040/3


Fibrosarcoma


8,810/3


Leiomyosarcoma


8,890/3


Liposarcoma


8,850/3


Malignant fibrous histiocytoma


8,830/3


Malignant mesenchymoma


8,990/3


Undifferentiated sarcoma


8,800/3


ICD-O, International Classification of Diseases for Oncology.


Source: From Schajowicz F, Sissons HA, Sobin. The World Health Organization’s histologic classification of bone tumors. A commentary on the second edition. Cancer. 1995;75:1208-1214, with permission.


Mesenchymal chondrosarcoma is seen in the skull as well as the bones of the trunk. This highly malignant tumor is composed of primitive mesenchymal cells focally differentiating in cartilage. The lesion is usually osteolytic with poorly defined limits and permeates cortex into soft tissues. A biphasic appearance is usual with two histologic patterns comprising sheets of dense small round or oval undifferentiated cells resembling Ewing sarcoma or lymphoma, alternating with a second pattern of easily identified cartilaginous tissue. Chondroid islands may appear quite abruptly among the undifferentiated cells that mimic early chondrogenesis, although more gradual transitions are also seen. Mitoses are frequent.


Ewing Sarcoma

Ewing sarcoma also amounts to about 10% of bone tumors but is exceptionally rare in the head and neck comprising 1% to 9% of all Ewing sarcoma.17 A cooperative Ewing sarcoma study of 301 cases recruited only 6 lesions affecting skull bones (2%) and 3 (1%) in the clavicles.18 The true cell of origin remains elusive, although it appears to arise from pluripotent mesenchymal tissue although a neuroectodermal origin is suspected.19,20 The histologic features are characterized by a structureless array of small hyperchromatic cells as one of the group of “small round blue cell” tumors. The diagnosis is established by additional measures beyond conventional light microscopy. For example, the majority of Ewing sarcomas (at least 80%) exhibit the specific translocation t(11;22)(q24;q12) between the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11. Alternate partners within the E-twenty-six (ETS) family are also present. Regardless of site, the treatment of all Ewing sarcoma mandates multiagent chemotherapy, in addition to local therapy, to reduce the likelihood of distant recurrent disease.


Grading Bone Sarcomas

As with STS, the grading of bone tumors provides an important prognostic measure and has been incorporated in the tumor, lymph node, metastasis (TNM) staging system discussed below.21

Osteosarcomas are graded according to the cell type and relative anaplasia of the stromal component of the tumor. Low-grade lesions (grade 1) may resemble parosteal osteosarcoma or fibrous dysplasia. Increasingly anaplastic tumors are given higher grades with the least well-differentiated tumors representing the highest grade. High-grade tumors (grade 3 or 4) generally comprise conventional (osteoblastic), telangiectatic, and dedifferentiated tumors. Chondroblastic and fibroblastic tumors are usually lower grade (grade 1 or 2).

The gross and microscopic appearance of chondrosarcoma varies according to the grade and anatomical site, which itself is often associated with grade. For chondrosarcoma, well-differentiated appearance (grade 1) is associated with longevity and favorable prognosis. For example, as mentioned earlier, tumors of the cricoid cartilage are invariably low grade as determined by cellularity, nuclear features, and mitotic activity. Metastasis is almost never seen and dedifferentiation to high-grade sarcoma is quite exceptional. In the NCDB report, progression to distant metastases was three times more likely to occur among higher-grade cases than the lower-grade cases. Overall, most cases in the NCDB series were grade 1 (50%) and grade 2 (37%) whereas only a minority were grades 3 and 4.16 Low-grade (well-differentiated) chondrosarcomas may also be difficult to discriminate histologically from benign cartilaginous lesions because they have the consistency of hyaline cartilage. Although most chondrosarcomas have a clearly dominant grade, multiple foci of different grade may be present and there is controversy about whether grading should only consider the highest grade identified within a tumor or be the predominant grade.16 Myxomatous changes with cystic degeneration in the tumor correlates well with a low or medium histologic grade though it is important not to confuse myxoid change in common chondrosarcoma with the myxoid chondrosarcoma variant.16 An absence of cartilaginous lobulation and the presence of spindle cell forms is characteristic of high-grade (grade 3) malignancy and heralds an unfavorable prognosis.

Of importance, Ewing sarcoma is always classified as high grade (and grade IV in the AJCC TNM classification).


ETIOLOGY AND SCREENING


Etiology

Apart from the diagnostic dilemma in distinguishing additional neurofibromata from metastatic lesions in patients with neurofibromatosis, the precise etiology of an individual sarcoma is of little clinical significance because it does not affect therapeutic decision making beyond the obvious fact that patients who have sarcomas arising in a previously irradiated field usually cannot receive further external-beam radiotherapy (EBRT). In fact, most sarcomas of the head and neck or elsewhere are without obvious cause. Of known factors, an induced STS and osteosarcoma is a long-term hazard of either iatrogenic or accidental exposure to radiation. Frequently, such tumors arise in the low-dose areas at the edge of prior radiation target volumes. Sarcomas have also been reported after chemotherapy, especially for pediatric cancers, such as acute lymphatic leukemia. The relative risk appears to increase with cumulative exposure to alkylating agents. Chemical exposure (usually occupational) is also linked to sarcoma causation being most recognized with thorotrast (x-ray technicians), vinyl chloride gas (plastics industry), phenoxy acetic acids (agricultural and forestry workers), chlorophenols (sawmill workers), and arsenic (vineyard work).

Association of rhabdomyosarcoma with genitourinary or central nervous system anomalies have been noted, as well as links to a variety of genetic conditions.22 Multiple factors are implicated in the etiology of angiosarcoma. Although the usual patient with a head and neck angiosarcoma will not manifest these, the disease is typically seen in the scalp and face of an elderly white male. In addition to prior radiation exposure, chronic infection or solar exposure have been implicated, as well as vinyl chloride, thorotrast, insecticides, and steroid exposure. There is up to a 10% cumulative lifetime risk of developing sarcoma (usually malignant peripheral nerve sheath tumor) in patients with type 1 neurofibromatosis, an autosomal dominant disease with dysfunction of the NF1 gene on chromosome 17q11.2.23 The NF1 gene product (neurofibromin) appears to be a tumor suppressor gene acting through GTPase activity with mutations leading to dysfunction and uncontrolled signaling via ras pathways. This may facilitate the development of malignant peripheral nerve sheath tumor.

Osteosarcoma (OS) has a number of risk factors. Exposure to radiation was noted earlier, but trauma and thorotrast exposure have also been described. OS may develop secondarily to underlying Paget disease, fibrous dysplasia, multiple osteochondromatosis, chronic osteomyelitis, and myositis ossificans. Retinoblastoma survivors provide a specific example of a dysfunctional or deleted tumor suppressor genetic element (in this case, the product of the Rb gene on chromosome 13q14) rendering these patients and their families at risk of soft tissue sarcoma, osteosarcoma (with or without radiotherapy) and several other malignancies including breast cancer. Alterations in p53 germlines are also associated with the high predisposition of families
with Li-Fraumeni syndrome for the development of osteosarcoma, again with or without radiotherapy.24

The etiology of chondrosarcoma remains obscure although various physical and chemical agents may be implicated. Speculation concerning undetermined dietary or environmental factors was prompted by the observation of a disproportionate incidence in low-income patients, although the mesenchymal subtype was more common among higher income groups.16 Chondrosarcoma (especially in the skull base) may complicate Maffucci syndrome, a congenital nonhereditary condition associating multiple cutaneous hemangiomas, dyschondroplasia, and often enchondromas (see Fig. 29-12B).25


Screening for Sarcomas

Predisposing genetic tendencies and environmental exposures associated with sarcoma development should be borne in mind when assessing patients. Genetic counseling would be appropriate to discuss issues relating to the genetic predispositions. However, no general screening is indicated beyond routine health care surveillance because of the rarity of sarcoma, with the rare exception of families suspected of carrying germline p53 abnormalities associated with Li-Fraumeni syndrome.26 A more detailed clinical evaluation in certain subjects is reasonable and with a lower threshold of intervention than one might use for general health care. For example, rapidly growing and/or symptomatic masses in patients with neurofibromatosis merit resection because of potential malignant transformation within a neurofibroma. Similarly painful and dramatic deformity in Paget disease should be viewed with concern about underlying osteosarcoma. Superficial or deep abnormalities of skin or soft tissues in patients with a history of prior radiation therapy should also be regarded with suspicion, given the known increased risk of sarcoma.


CLINICAL PRESENTATION, EVALUATION, STAGE CLASSIFICATIONS


Local Presentation

Sarcomas of the head and neck present in multiple ways depending on the numerous potential anatomic sites where disruption of function and contour may result. Local management starts with imaging and physical examination to determine whether soft tissue lesions originate superficial or deep to the investing fascia at the local site and whether bone tumors are intramedullary or have invaded into the extraosseous compartment. Evidence of bone, vascular, or neural invasion (uncommon) should be excluded.

Lesions may originate in the upper aerodigestive tract, paranasal sinus, and skull base with symptoms referable to these areas (e.g., nasal symptoms including obstruction or discharge and ocular proptosis from direct invasion in paranasal sinus tumors; cranial nerve abnormalities in lesions arising in the skull base or masticator space; alteration of voice or airway compromise for laryngeal and hypopharyngeal lesion lesions). Tumors originating in the subcutaneous tissues of the face, neck, or scalp can initially present with a superficial mass.

Both bone and cartilage tumors often present with pain in addition to symptoms of mass and compression. Pain generally relates to infiltration and expansion of bone. In lower-grade lesions, pain can be of long duration and characterized as a prolonged aching sensation, sometimes present for several years. Most often, they present as a slow growing mass or with looseness of dentition. Because of the potential to also arise in the skull base and paranasal sinuses, a wide variety of symptoms are also possible, depending on tumor site. These include cranial neuropathy and visual disturbance (including ophthalmoplegia and proptosis) in addition to pain, the latter being evident in about half the cases.


Metastatic Manifestations

Most sarcomas present with localized disease and metastases are present in only 10% of cases at the time of diagnosis. Generally, the patient is asymptomatic and staging investigations (computed tomography [CT] chest) are needed to demonstrate the metastatic process as the predominant risk is to the lungs. Regional lymph node involvement is unusual but is represented most frequently in certain histologic subtypes, most notably rhabdomyosarcoma, epithelioid, alveolar soft part, clear cell, and synovial sarcomas. Rarely, remote bone marrow metastases are apparent but are seen almost exclusively in rhabdomyosarcoma with associated lymphadenopathy. In osteosarcoma, bone metastases may be present in the absence of lung involvement but this is exceptional.


Evaluation

Initial Assessment. Successful outcome starts with reliance on basic principles and understanding the behavior of the disease and the necessary steps to be undertaken. The overall management of head and neck soft tissue sarcoma is summarized in the treatment algorithm (Fig. 29-3). Before embarking on treatment, histologic confirmation of the diagnosis is necessary. All soft tissue masses deep to the investing fascia should be considered to be sarcoma until proven otherwise. The same vigilance is needed for bone lesions but here the opinion of an experienced diagnostic radiologist is required. Both bone and soft tissue lesions should be staged with cross-sectional imaging before the biopsy to avoid compromising the planning of appropriate management.

Establishing the Diagnosis. Fine-needle aspiration biopsy (FNAB) is useful for establishing the presence of recurrence (both local and metastatic). However, its use as a primary diagnostic tool is controversial and should only be used where a cytopathologist with extensive experience in sarcoma is available. Core-needle biopsy under local anesthesia provides a more consistent tissue specimen and cell preparation compared with fine-needle aspiration. In our experience, open biopsy of soft tissue sarcoma is rarely indicated but yields a diagnosis when needle biopsy is unsuccessful (about 10% of cases).

Interventional radiologists are often requested to biopsy deepseated lesions using ultrasound or CT guidance. An atraumatic biopsy close to critical structures or where the lesion is difficult to palpate can be accomplished. The radiologist should collaborate with the oncologists who will resect or irradiate the lesion. Needle tracts are potential sites of tumor contamination and the surgeon and radiation oncologist should be involved in planning the optimal biopsy route and be aware of potential contamination.

Imaging Local Disease. Both CT scan and magnetic resonance imaging (MRI) are used widely. CT provides better bony detail than MRI, but MRI provides multiplanar images without losing specificity and is likely the best instrument for tumor definition with optimal tissue contrast. Therefore, in those situation where it is important to visualize the matrix of a lesion, CT is preferred. This usually occurs in flat bones including the calvarium. Plain radiography is also useful for bony lesions but has largely been replaced by CT. Both have the advantage of exhibiting calcification in tumor which may be characteristic of certain histologies (e.g., chondrosarcoma and synovial sarcoma). Malignant bone lesions will frequently present with marked permeative bone destruction, illdefined transition to normal bone, aggressive periosteal reaction,
and an accompanying soft tissue mass. In the end, it is our impression that MRI generally provides superior depiction of intraand extraosseous tumor in most malignant tumors of bone. Axial imaging complemented by either coronal or sagittal imaging planes using T1- and T2-weighted SPIN echo sequences most often provides accurate depiction of intra- and extraosseous tumor. To improve conspicuity, these sequences could be augmented by fat-suppressed pulse sequences. The maximum dimension of the tumor must be measured prior to any treatment.






FIGURE 29-3. Flow schema for the assessment and management of soft tissue sarcoma (STS) of the head and neck. Because of the heterogeneity of tumor and anatomical sites, individualization is also needed. Thus some diseases, such as rhabdomyosarcoma, may need additional investigations (e.g., bone marrow examination)— see text for details of management. MRI, magnetic resonance imaging; CT, computed tomography; AJCC, American Joint Committee for Cancer; UICC, International Union Against Cancer; TNM, tumor, node, metastasis; RT, radiation therapy.

In soft tissue sarcoma, low signal intensity on T1-weighted images and a high signal on T2-weighted images are the usual appearances and can be readily separated from normal soft tissue structures. Again lesion size should be recorded.

Although the diagnostic evaluation may be equally served by CT or MRI, the treatment-planning requirements (e.g., for both surgery and radiotherapy) frequently require additional information provided by the multiplanar capability of MRI and provides additional advantages through MRI/CT image-fusion techniques for radiotherapy treatment planning (Fig. 29-4).

Radionuclide bone scanning is a sensitive indicator of osteoblastic activity but lacks specificity. It can demonstrate multiple lesions but may also overestimate the extent of intramedullary infiltration when compared with MRI scanning.

Positron emission tomography (PET) uses radiotracers specific to biologic processes to produce images of regional tissue metabolism with fluorodeoxyglucose, the most commonly employed radiotracer for this purpose. However, the contribution of PET imaging to routine management is currently uncertain. New tracers are being evaluated that may refine the differing roles for PET imaging that include evaluation of (a) the grade and extent of local disease including the potential for “skip” lesions in adjacent bone and (b) the response to initial (i.e., neoadjuvant) treatment as a surrogate to prognosticate on future outcome. It does seem that high- versus low-grade lesions may be distinguished and may even provide an imaging technique for biopsy guidance; in addition, response prediction to induction treatments seems to be possible.27,28,29,30

Evaluation of Metastasis. For metastatic staging, CT of the chest is required, excepting very low-grade lesions where a plain chest radiograph is sufficient. If the underlying diagnosis is rhabdomyosarcoma, a bone scan and bone marrow biopsy is also necessary. Angiography is only rarely required in the evaluation of sarcomas. PET scan is also not widely used but may have applicability in identifying unusual sites of metastases in high-risk subsets (e.g., recurrent high-grade tumors).31 Technetium scintigraphy is the examination of choice for evaluating the entire skeleton to determine whether there are multiple lesions and is particularly important for diseases with high propensity for bone metastasis such as Ewing sarcoma. Occasionally, intrapulmonary osteoblastic metastases may be demonstrated.


Staging Classifications

Both soft tissue and bone sarcomas are classified according to the TNM stage classification (7th edition).21 The classification has provided the possibility of combining a number of relevant factors including those addressing behavior (by means of inclusion
of grade) and anatomic factors.32 However, a major limitation of the staging system is that it does not take into account the anatomic and histologic heterogeneity of these lesions. The system is also optimally designed to stage extremity tumors and is also applicable to the head and neck although lacks subtlety since the T-category size criterion dwarfs the anatomic sites of origin in the head and neck, which tend to be much smaller. An additional issue concerns rhabdomyosarcoma, where two separate descriptions of disease extent exist.






FIGURE 29-4. A: Magnetic resonance image (MRI) used for fusion in the axial plane for computed tomography (CT) intensity-modulated radiotherapy (IMRT) planning of an unresectable malignant fibrous histiocytoma of the right base of skull. Shown are the 66.5 Gy isodose (95% of the prescribed dose of 70 Gy in 35 fractions) and the 56 Gy peripheral isodose line for radical IMRT for this lesion. MRI imaging shown on the right side is far superior to the CT planning data set on the left in delineating the lesion depicted as the gross tumor volume (GTV) in red in both images. B: The sagittal view of the radiotherapy plan shows the 66.5 Gy isodose (95% of the prescribed dose of 70 Gy in 35 fractions) and the 56 Gy peripheral isodose line for a course of radical radiotherapy alone in this patient. There is dose reduction to protect the optic chiasm using IMRT (arrow). C: The initial coronal MRI is shown with an enhancing mass centered along the right lateral wall of the sphenoid sinus and projecting medially into the sphenoid sinus and laterally into the middle cranial fossa. The lesion was considered unresectable because of involvement of the cavernous sinus with encasement of the right internal carotid artery. D: The patient experienced a complete response to fractionated photon irradiation using IMRT delivered stereotactically with 3-year follow-up and is currently asymptomatic without evidence of disease.







FIGURE 29-4. Continued


Soft Tissue Sarcoma

“Ordinary” Soft Tissue Sarcoma. The relative rarity of STS, the anatomic heterogeneity of these lesions, and the presence of >30 recognized histologic subtypes of variable grade have made it difficult to establish a functional system that can accurately stage all forms of this disease. The American Joint Committee on Cancer (AJCC) TNM (7th edition) staging system21 is the most widely employed staging system for STS and is unusual within the overall TNM classification system in that, like the bone classification, it incorporates histologic grade with anatomical disease characteristics. The soft tissue classification employs a three-tiered grading system based largely on the wish to incorporate the French system.21 In general, the classification is based on an ascending hierarchy of risk depending on whether a lesion is deemed to have no adverse features for relapse or one, two, or three factors present represented by size partitioned at the 5-cm break point, grade (three-tiered system), and lesion depth as “a” (superficial tumor arising outside the investing fascia) or “b” (a deep tumor that arises beneath the fascia or invades the fascia) (Table 29.4).

Rhabdomyosarcoma. For nonpleomorphic rhabdomyosarcoma (RMS), the description of disease extent has traditionally been by a postoperative surgical classification developed by the North American Intergroup Rhabdomyosarcoma Study Group (IRSG) more than two decades ago (Table 29.5). This is not always relevant in the head and neck as such lesions will frequently be treated with aggressive chemoradiotherapy protocols (Fig. 29-5). Indeed, most lesions would be unresectable and thus classified as group III at diagnosis. They are most often parameningeal in location, considered an “unfavorable” site by the IRSG system, and thus labeled as stage 3. The International Society of Pediatric Oncology (SIOP) has suggested a TNM presurgical staging system more in keeping with contemporary TNM staging for soft tissue sarcoma including a T-category breakpoint at 5 cm (Table 29.6).33 This process of staging prior to treatment is also being introduced in North America.22 Regardless
of the classification used, adequate imaging of regional lymph nodes is imperative in patients in RMS.








TABLE 29.4 American Joint Committee on Cancer (AJCC) TNM Classification (7th Edition) of Soft Tissue Sarcomas







































































































Primary tumor (T)


TX


Primary tumor cannot be assessed


TO


No evidence of primary tumor


T1


Tumor 5 cm or less in greatest dimension



T1a, superficial tumor



T2b, deep tumor


T2


Tumor >5 cm in greatest dimension



T2a, superficial tumor



T2b, deep tumor


Note: Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia.


Regional lymph nodes (N)


NX


Regional lymph nodes cannot be assessed


NO


No regional lymph node metastasis


N1


Regional lymph node metastasis


Note: Presence of positive nodes (N1) in MO tumors is considered Stage III.


Distant metastasis (M)


MX


Distant metastasis cannot be assessed


MO


No distant metastasis


MI


Distant metastasis


Stage grouping


Stage IA


G1


T1a, 1b


NO


MO


Stage IB


G1


T2a, 2b


NO


MO


Stage IIA


G2-3


T1a, 1b


NO


MO


Stage IIB


G2


T2a, 2b


NO


MO


Stage III


G3


T2a, T2b


NO


MO



Any G


Any T


N1


MO


Stage IV


Any G


Any T


Any N


M1


G, Grade.


Source: From Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010, with permission.









TABLE 29.5 Intergroup Rhabdomyosarcoma Study Group Postsurgical Grouping Classification


























Group 1: Localized disease, completely excised and no residual microscopic disease


A.


Confined to the site of origin, completely resected


B.


Infiltrating beyond site of origin, completely resected


Group 2: Total gross resection


A.


Gross resection with evidence of microscopic local residual disease


B.


Regional disease with involved lymph nodes, completely resected with no microscopic residual disease


C.


Microscopic local and/or nodal residual disease


Group 3: Incomplete resection or biopsy with gross residual disease


Group 4: Distant metastases


Bone Sarcoma. The AJCC TNM classification of bone tumors (Table 29.7) considers maximum lesion size (with a break point at 8 cm) and the presence discontinuous tumors in the same bone without other distant metastasis. Of interest, metastasis to nonpulmonary sits are distinguished from M1 disease based on lung involvement alone. The staging system is applicable to all primary malignant tumors of bone except multiple myeloma, malignant lymphoma (both having different natural history), and juxtacortical osteosarcoma and chondrosarcoma (both with much more favorable prognosis).21






FIGURE 29-5. Magnetic resonance image of an alveolar rhabdomyosarcoma of the ethmoid sinus in a young adult. A: coronal view showing extensive orbital invasion; B: axial view showing concurrent extensive regional lymphadenopathy; C: complete response following combination chemotherapy with cyclophosphamide, actinomycin-D, vincristine (CAV), and etoposide with ifosfamide. Although consolidation radiotherapy commonly achieves local-regional control in these responsive tumors, such patients are at extremely high risk of failure in bone marrow, lung, and leptomeningeal sites.


TREATMENT OF SOFT TISSUE SARCOMA

The benchmark for local control rates for extremity sarcomas rests at approximately 90% in modern series, and the overall 5-year survival of patients with STS can be expected to be in the range of 60%,34 although this will vary as a function of prognostic factors from case to case. Unfortunately, series of head and neck sarcoma have usually not achieved these high local control rates. Mendenhall et al.35 recently performed a systematic literature review and showed that the local control rate after surgery alone or combined with radiotherapy is approximately 60% to 70%. The probability of local control is influenced by histologic grade, tumor size, and surgical margins. Patients with high-grade tumors and/or positive margins have improved local control if adjuvant radiotherapy is used. Distant metastases manifest in about 10% to 30% of patients, figures that are somewhat lower than extremity lesions and is probably explained by the smaller size of lesion in the head and neck that presents earlier due to proximity to critical functional and cosmetic anatomy. The 5-year overall and cause-specific survival rates ranges from 60% to 70% and seems to be influenced by age, histologic grade, previous treatment of tumor, invasion of deep structures, and adequacy of surgery. The disappointing results in head and neck STS has been attributed to the traditional
inability to deliver aggressive treatments because of their location in the critical anatomy of the head and neck. It may also relate to problems in delivering care for these rare diseases, if undertaken in the absence of a full multidisciplinary team. However, properly deployed principles and approaches should be able to achieve results in the head and neck that are comparable to similar lesions in extremity sites. Several randomized controlled trials have collectively established important milestones in the evolution of the local management of STS. With one exception, these trials have focused on extremity lesions and around the themes of surgery and adjuvant radiotherapy. These results are also highly relevant to the head and neck because of the similarity of biologic behavior of STS across body sites, even if the different histologic subtypes are not equally distributed by site.






FIGURE 29-5. Continued








TABLE 29.6 International Society of Pediatric Oncology (SIOP) Presurgical Staging Classification (Clinical and Radiologic Staging)
































Stage


Tumor


Node


Metastases


I


T1a or T1b


NO, Nx


M0


II


T2a or T2b


NO, Nx


M0


III


Ant T


N1


M0


IV


Any T


Any N


M1


T1, Confined to the anatomic site of origin; T2, Extension and/or fixation to surrounding tissue; (a), <5 centimeters in diameter; (b), >5 centimeters in diameter; Nx, Unknown nodal status; NO, No nodes present clinically; N1, Regional nodes present; Mo, No distal metastasis; Mo, Metastasis present.


Source: From Stevens MCG. Malignant mesenchymal tumours of childhood. In: Souhami RL, Tannock I, Hohenberger P, et al., eds. Oxford Textbook of Oncology. 2nd ed. Oxford, UK: Oxford University Press; 2002:2525-2538, with permission.









TABLE 29.7 American Joint Committee on Cancer (AJCC) TNM Classification (7th Edition) of Bone Sarcomas






































































































Primary tumor (T)


TX


Primary tumor cannot be assessed


TO


No evidence of primary tumor


T1


Tumor (maximum dimension) ≤8 cm at time of diagnosis


T2


Tumor (maximum dimension) >8 cm at time of diagnosis


T3


Skip metastases-two discontinuous tumors in the same bone with no other distant metastases


Regional lymph nodes (N)


NX


Regional lymph nodes cannot be assessed


NO


No regional lymph node metastasis


N1


Regional lymph node metastasis to be considered equivalent to distant metastatic disease (see M1b below)


Note: Because of the rarity of lymph node involvement in sarcomas, the designation NX may not be appropriate and could be considered NO if no clinical involvement is evident.


Distant Metastasis (M)


MX = Distant metastasis cannot be assessed


MO = No distant metastasis


M1 = Distant metastasis



M1a = Lung-only metastases



M1b = All other distant metastases including lymph nodes


Stage Grouping


Stage IA


G1,2


T1


NO


MO


Stage IB


G1,2


T2


NO


MO




G1,2


T3


NO


MO


Stage IIA


G3,4


T1


NO


MO


Stage IIB


G3,4


T2


NO


MO


Stage III


G3,4


T3


NO


MO


Stage IVA


Any G


Any T


NO


M1a


Stage IVB


Any G


Any T


NO/N1


M1b


G, Grade.


Source: From Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010, with permission.




Surgery

Major Ablation Versus Conservation Management. In the 1970s, it became apparent that RT in combination with surgery could achieve equivalent results to more ablative surgery in STS. This observation was confirmed in a trial that randomized high-grade sarcoma of the extremities to receive amputation versus a limbsparing operation followed by adjuvant RT.36 The result of this trial, combined with numerous institutional reports, heralded a new era in STS management.

Extent of Surgery and Characterization of Margins. An important component of contemporary management is the value of imaging in demonstrating the radial extent of sarcoma within the compartment or site of origin and, together with radiotherapy, permits conservation of much of the surrounding soft tissue without increased local failure. Of more importance than the description of the type of surgery is the actual extent of viable residual disease remaining after surgery. This variable (the amount of residual viable disease remaining in the wound following resection) can never be known exactly, but is probably best represented by expert pathologic assessment of the surgical margin. Characterization of the margin guides the need for adjuvant RT for those tumors with insufficient normal tissue at the surface to reliably prevent local recurrence. Patients with positive margins of resection have inferior local control in STS and this prevails in the head and neck to the same degree as in other sites.37

The cause of positive margins is rarely discussed. The policy in STS surgery should be to achieve negative surgical margins, and this is best achieved by performing surgery at an experienced referral center. More recently, we have also shown, in a blinded study using a prospective data base, that a small isolated positive resection margin, planned from the outset by the multidisciplinary team with the intention of sparing a critical anatomic structure (e.g., at a major nerve, vessel, or bone), has a favorable outcome provided radiotherapy is administered (local recurrence 3.6%, 95% CI, 0-10.4) compared with an “unplanned excision” margin-positive situation (local recurrence 31.6%, 95% CI, 10.7-52.5).38 Substantial contamination with tumor seeding in a hypoxic environment may mean that subsequent radiotherapy is less capable of eliminating tumor seeding in the “unplanned excision” circumstance.

Evidence for Using Surgery Alone. Although the evidence is compelling that major ablation is avoidable in most cases, it is also helpful to consider whether adjuvant radiotherapy is needed to achieve conservation management, in comparison with surgery alone. This issue is complicated by case heterogeneity but a subgroup of patients undoubtedly do not need RT based on several sources of evidence, although none reported in the head and neck specifically. These rely on single-institutional experience with practices involving degrees of selection including subcutaneous or intramuscular presentation, or extramuscular lesions with favorable resection margin status. However, most deep sarcomas in all sites are referred with lesions significantly expanding out of a single muscle unit or have undergone biopsy prior to referral and therefore need radiotherapy combined with surgery. The approach is less applicable in the head and neck because the proximity to critical anatomy makes it less likely to achieve sufficient clearance to have confidence that surgery alone would eradicate disease, and there remains the added concern that local failure in head and neck STS confers extremely adverse outcome. The latter includes mortality directly from progressive local disease,39 a phenomenon not relevant to extremity lesions.






FIGURE 29-6. Actuarial estimate of local control rate in soft tissue sarcoma of the head and neck by surgical margins. Histopathologically clear (solid line), microscopically positive (dotted line), and gross disease (dashed) line are shown for patients treated with curative intent following surgical resection.

Source: Data reproduced with permission from Le Vay J, O’Sullivan B, Catton C, et al. An assessment of prognostic factors in soft-tissue sarcoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1994;120:981-986.


Radiotherapy

Adjuvant Radiotherapy. Adjuvant RT with conservative surgical resection has been evaluated in two randomized clinical trials.40,41 Yang et al. at the National Cancer Institute (NCI) randomized highgrade extremity lesions following limb-sparing surgery to receive adjuvant RT or no further treatment following the surgery. Chemotherapy was also used depending on grade. The local control for those receiving RT was 99% compared with 70% in the control group (p = 0.0001).41 The results were similar for high- and lowgrade tumors. Adjuvant RT, using brachytherapy (BRT), was also evaluated in a second randomized trial at Memorial Sloan-Kettering Cancer Center with a similar effect in high-grade lesions.40 Of interest, no improvement in local control was evident in the low-grade tumors, potentially related to slowly cycling cells not entering the radiosensitive phases of the cycle during the short BRT-dwell time.40

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