Simple Karyotypic Sarcomas with Specific Genetic Alterations

The first group, those characterized by specific recurrent chromosomal translocations, comprises approximately one third of all sarcomas, and the resulting product of the specific gene fusions usually encode aberrant chimeric transcription factors. These translocations are often the only cytogenetic abnormalities and appear to be pathogenetically important. However, although successful cloning of most genes involved in recurrent translocations has taken place, there remains a paucity of information about the downstream targets mediating oncogenic transformation. In general, the promiscuous pairing of a proximal gene that contributes a promoter and functional domain, with a distal gene possessing a DNA binding domain that confers target specificity, determines the phenotype of various STS.²⁷ Most translocations result in the production of a tumor-specific RNA that encodes a novel transcription factor that plays a role in oncogenesis in mesenchymal cells.

One uncommon mechanism results in a chimeric autocrine growth factor and is evident in dermatofibrosarcoma protuberans (DFSP) in which the t(17;22)(q22;q13) translocation involving the COL1A1-PDGFB genes provides a therapeutic target for response to the tyrosine kinase inhibitor imatinib. Mechanisms such as this represent opportunities for future management. At this time, however, they are typically used in a diagnostic manner to identify a particular subtype of tumor. This is the case for synovial sarcomas, nearly all of which exhibit the t(X;18)(p11;q11) translocation and can be distinguished from other tumors with similar morphology, such as a malignant peripheral nerve sheath tumor. Another example is the fusion product PAX3-FOXO1 arising from the t(2;13)(q35;q14) translocation as well as the t(1;13)(p36;q14) translocation expressed in alveolar rhabdomyosarcoma²⁷ (Table 63-1).

TABLE 63-1 Cytogenetic Abnormalities and Fusion Genes in Soft Tissue Sarcoma

Complex Karyotypic Sarcomas without Specific Genetic Alterations

The remaining two thirds of STS lack a recurrent genetic signature and are characterized by numerous aberrations, including chromosomal losses and gains. Most adult spindle cell tumors, leiomyosarcoma, and pleomorphic sarcomas belong to this group. At the molecular level, this sarcoma subset features a high prevalence of TP53 checkpoint alterations, including TP53 inactivating mutations, homozygous deletion of CDKN2A, MDM2 amplifications, and so on. Unfortunately, most cases with complex karyotypes and multiple aberrations do not have a consistent correlation with pathologic or clinical parameters. There also appears to be no indication in most of these lesions that detectable genetic alterations might be useful either for diagnosis or prognosis.²⁹

Genetic Conditions Associated with Sarcomas

Given the genetic information just presented, it is not surprising that STS are associated with several genetic conditions. Patients with neurofibromatosis have a 5% to 10% lifetime risk of developing a malignant neurofibrosarcoma arising in a neurofibroma,^30–33 most commonly in the central nervous system. These patients frequently present the additional diagnostic dilemma of distinguishing between potential metastases or other benign neurofibromas found on staging investigations.

A significant risk for STS is found in individuals with somatic mutations in the TP53 tumor suppressor gene, including Li-Fraumeni syndrome, which is characterized by a familial cluster of sarcoma (12%), breast cancer (25%), leukemia, adrenal carcinoma, brain tumors (12%), lung cancer, skin cancer, and pancreatic cancer.^34,35

Long-term survivors of retinoblastoma with the associated RB gene abnormality often develop tumors later in life, with a risk of 10% to 15%.^36,37 For hereditary retinoblastoma, the cumulative incidence of a second cancer at 50 years after diagnosis is 50% compared with only 5% for nonhereditary retinoblastoma.³⁸ Wong and associates³⁸ showed that the relative risk of STS increases with dose beginning at 5 Gy, rising to 10.7-fold at dose levels exceeding 60 Gy.

Gardner’s syndrome, a subset of familial adenomatous polyposis, is associated with the development of intra-abdominal desmoids.³⁹

Classic Pathology Classification

While originating from the mesoderm and in some lesions from ectoderm, a beguiling feature of the legacy of the nomenclature of sarcoma pathology is the traditional view of histologic subtypes originating from similar-appearing normal tissue counterparts. The most common classification scheme for STS is still based on histogenesis, as described by the World Health Organization (WHO) and others52,53,54 (Table 63-2). However, as the degree of histologic differentiation becomes less apparent, the determination of a putative cellular origin becomes increasingly difficult.

TABLE 63-2 Histologic Classification of Soft Tissue Sarcoma*

* Benign lesions other than fibromatosis and atypical lipoma are not included in the present tabulation.

Adapted from references 52, 53, and 54.

This view of pathogenesis and histogenesis is now being contested. Although some benign lesions (especially lipomas) may resemble mature differentiated normal tissue, many STS arise in tissues that do not typically possess the putative normal tissues mentioned. For example, synovial sarcomas are only rarely found in synovial tissues. Because the necessary genetic information is contained in all diploid cells, a more plausible explanation may be that a given set of genes may program differentiation in any mesenchymal cell, thereby giving origin to almost any mesenchymal neoplasm.52,53,54 It seems unlikely that there is a single precursor primitive mesenchymal stem cell for each sarcoma.

Classification by Functional Genomics

With advances in molecular characterization of STS, and the emerging dissatisfaction with traditional methods of classification, it is not unexpected that recent proposals have explored gene expression profiling for these tumors (Fig. 63-1) to attempt to identify a genome-based classification scheme.^{55,56,57,58,59,60} For example, Segal and colleagues⁵⁹ examined RNA sarcoma samples and found that synovial sarcomas, round-cell/myxoid liposarcomas, clear cell sarcomas, and gastrointestinal stromal tumors (GIST) displayed distinct and homogeneous gene expression profiles. In a separate study, Nielsen and colleagues⁵⁸ observed that KIT appeared to be one of the prominent discriminator genes for malignant fibrous histiocytoma. More recently, Nakayama and co-workers⁵⁷ have shown that many neoplasms initially (mis)classified as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma based on their morphology and immunoprofile could be reclassified as myxofibrosarcoma based on gene expression, suggesting that gene profiling will be a useful tool to aid histologic diagnosis of malignant fibrous histiocytoma. Two genes, GPR64 and TNXB, were particularly expressed by myxofibrosarcomas but not by undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma, thus allowing distinction between these two histotypes.

Figure 63-1 Clustered expression measurements of 4766 genes from 81 soft tissue sarcomas. Expression measures were median centered before cluster analysis using the centered Pearson correlation coefficient. MLS, myxoid liposarcoma (n = 16); SS, synovial sarcoma (n = 18); LMS, leiomyosarcoma (n = 25); MFH, malignant fibrous histiocytoma (n = 13); LPS, dedifferentiated liposarcoma (n = 9).

Courtesy Neal Poulin and Torsten Nielsen of the Musculoskeletal Tumor Group, British Columbia Cancer Agency.

New molecular technologies such as comparative genomic hybridization array–based techniques and gene expression analyses show promise for the identification of genes, gene products, and signaling pathways involved in the pathogenesis, progression, and metastatic dissemination of sarcomas that may provide new strategies for the enhancement of local/systemic control and the reduction of the toxic effects of sarcoma management.⁵⁶ In particular, nanotechnology offers countless opportunities for novel diagnostic and therapeutic approaches to selectively target tumors at the cellular level.⁶⁰

Grading of Sarcoma

In the diagnostic pathology of sarcoma, the actual histologic subtype of sarcoma is usually overshadowed in prognostic importance by the designation of pathologic grade. Grade provides a means to identify cases at greatest risk for distant metastasis when combined with other factors. This is important because it provides a means to consider many patients for more intensive treatment approaches or at least to permit a rational approach to clinical trial design to evaluate the role of systemic adjuvant treatments to prevent distant metastases.

Several grading schemes have been proposed and validated as efficacious and are discussed in detail elsewhere.⁶¹ The three-tier system proposed by the French Federation of Cancer Centres is precisely defined, easy to use, and the 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. Roughly defined as the extent to which a lesion resembles normal tissue, differentiation score has little applicability for tumors that ostensibly have no normal tissue counterpart. It is also recognized that no system performs perfectly in all sarcomas. In one review, Deyrup and Weiss⁶¹ highlighted problems, including the fact that some STS do not lend themselves well to grading. These include (1) those in which grade provides no additional information (e.g., well-differentiated liposarcoma/atypical lipomatous neoplasm, Ewing’s sarcoma); (2) “ungradable” histologic subtypes (e.g., epithelioid sarcoma, clear cell sarcoma, angiosarcoma); and (3) 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).

In addition to the French system, there is a U.S. National Cancer Institute (NCI) system.⁶² Both use degrees of necrosis and mitotic rate, but the American system considers histologic type or subtype, location, cellularity, and nuclear pleomorphism. The situation is further complicated by the potential use of different tiers of grade within existing classification systems (e.g., two-, three- and four-grade classification systems). The TNM stage classification of the American Joint Committee on Cancer (AJCC) now employs a three-tiered grading system based largely on the wish to incorporate the French system.⁶³

Malignant Fibrous Histiocytoma

Since the late 1970s malignant fibrous histiocytoma has borne the mantle of most common STS of middle and late adulthood and therefore warrants specific mention in the chapter. Originally described in the 1960s, the term was used to describe a group of sarcomas deemed to be derived from a mixed histiocytic and fibroblastic lineage. The existence of ‘‘malignant fibrous histiocytoma’’ as a distinct entity is now considered controversial and at best is regarded as a heterogeneous group of tumors without a specific known line of differentiation. Most of these tumors were considered to be either a variable storiform and/or undifferentiated pleomorphic phenotype or one of four rarer additional types: myxoid (the next most common subtype), giant cell, inflammatory, and angiomatoid (a rare variant and the only one to survive contemporary reclassification). Reclassification of many tumors in this group has afforded better prognostication, and the old term “malignant fibrous histiocytoma” now is generally considered obsolete.⁵⁴

Current nomenclature recognizes the entities of undifferentiated high-grade pleomorphic sarcoma (previously storiform-pleomorphic “malignant fibrous histiocytoma”) and myxofibrosarcoma (formerly myxoid “malignant fibrous histiocytoma”), which is now the most common sarcoma of older adults, peaking in incidence in the seventh and eighth decades and presenting most frequently in the lower extremity. Most of these tumors are deep seated, developing in fascia and skeletal muscle, and have a high potential for local recurrence.54,56 Low-grade myxofibrosarcoma is known to have a particularly infiltrative growth pattern, and imaging evaluation with particular attention to tail-like extensions should be considered for management.⁶⁴ This type must be differentiated from other sarcomas containing myxoid areas, such as pleomorphic liposarcoma. The feature that sets malignant fibrous histiocytoma lesions apart is the absence of a defined line of differentiation from which epithelial, melanotic, and lymphoid differentiations have been excluded.⁵²

The natural history is extraordinarily variable, reflecting the heterogeneity of these lesions. The most common site for metastases from pleomorphic sarcomas is the lung (90%), bone (8%), and liver (1%), with rare regional lymph node metastases.⁵⁴

Angiosarcoma

Angiosarcoma is currently included in the seventh edition of the TNM stage classification.⁶³ Particularly unique is the propensity of superficial angiosarcoma to occur in the dermal tissues of the head and neck manifesting typically on the scalp (about 50%) or facial skin. These neoplasms commonly present as purple, bruiselike lesions in elderly white men and are rarely seen in patients of African origin.⁶⁵ The macules usually become nodular, may coalesce, and may ulcerate. Frank bleeding is an ongoing and major problem and often results in chronic oozing through dressings. A particularly difficult aspect of management is the apparent multifocal nature that makes judgment about the area of risk almost impossible from the standpoint of accurate definition of margins for both surgery or RT. The clinical examination must be meticulous because it is the only real means of identifying the deceptive areas of multifocal involvement that may exist.⁶⁶ Frequently, individual patches coalesce into flat masses of substantial size. Involvement of the eyelid and periorbital tissues is particularly troublesome. Metastasis is common if patients survive sufficiently long and occurs most typically in regional lymph nodes and the lung.

The majority of angiosarcomas are considered to originate from the endothelium of the blood vasculature.⁶⁷ Koch and colleagues⁶⁸ have outlined the pathologic features, which can range from well to poorly differentiated lesions. They are typically composed of an accumulation of an irregular or sinusoidal pattern of vessel with vascular spaces lined by a single row of atypical endothelium that may be several layers thick. Highly cellular lesions can manifest as sheets of cells with vascular space obliteration that contribute solid components as vascular channels effaced by the crowding of cells. High-grade, poorly differentiated lesions can be composed of undifferentiated cells and disordered architecture, making them difficult to discern from other histologies, although the hallmark clinical presentation and behavior generally leave little doubt about the diagnosis. On immunohistochemistry, these tumors are usually positive for factor VIII–related antigen, vimentin, CD34, and CD31.

It is suggested that angiogenesis and vascular permeability play a central role in the development of angiosarcomas. This is likely influenced by vascular endothelial growth factor A (VEGF-A), which plays a significant role in angiogenesis and vascular permeability. VEGF-A induces angiogenesis by acting through a tyrosine kinase receptor predominantly found on vascular endothelial cells, including VEGF receptor-1. VEGF-A acts to enhance the growth of tumors by promoting a more extensive blood vessel supply and increases the probability of hematogenous metastases. Similarly, it has been proposed that angiogenesis and vascular permeability play a central role in development of angiosarcomas, suggesting a role for VEGF-A in the pathogenesis of angiosarcomas,⁶⁷ thereby opening the potential for molecular targeted agents in the future. Bevacizumab, a humanized monoclonal antibody to VEGF, is an attractive agent to consider in angiosarcoma, given its ability to inhibit tumor growth. Koontz and coworkers⁶⁹ have reported promising results in two patients using neoadjuvant bevacizumab combined with RT.

Another rare variant is one complicating the treatment of breast carcinoma, with superficial angiosarcoma appearing extensively within the confines of the previously irradiated volume and a tendency to develop disease in the opposite breast. A further interesting predisposition in angiosarcoma is its tendency to arise in cardiac tissues, where it represents one of the most common pathologic subtypes of a rare presentation of STS.

Rhabdomyosarcoma

Rhabdomyosarcoma is especially important because it is the fifth most common cancer in childhood,⁷⁰ but it also occurs in the adult, where the outcome is significantly less favorable.⁷¹ One feature concerns the “spindle cell rhabdomyosarcoma” that is only rarely described in the adult compared with children and carries a relatively favorable prognosis. In the adult it appears to have a predilection for the head and neck and may be unusually aggressive.^72,73 The rhabdomyosarcoma classification recognizes embryonal, botryoid, alveolar, and pleomorphic subtypes for both childhood and adult cases. Rhabdomyosarcoma can be recognized on light microscopy by the presence of cross striations within cytoplasmic fibrils of spindle-shaped cells that typically demonstrate immunostaining for myogenic markers.⁷⁴ Seventy percent of rhabdomyosarcomas can be classified as embryonal and 20% alveolar, and the remainder are variants, including the uncommon pleomorphic subtype. The pleomorphic subtype is almost never seen in the pediatric population and is not considered in those classifications; there is debate about whether it truly represents part of the disease process and it may fall into the “malignant fibrous histiocytoma” type categories described earlier.

Embryonal rhabdomyosarcoma has variable amounts of primitive spindle or round cells in a myxoid background. These rhabdomyoblasts appear in a variety of unusual shapes called “tadpole” or “strap” cells. Cross striations on light microscopy can be seen in half of these cells. The botryoid rhabdomyosarcoma is thought to be a variant of the embryonal type and only accounts for 5% of cases. It is defined as a tumor having polypoid morphology with the presence of subepithelial aggregates of malignant cells, referred to as the cambium layer. Botryoid tumors have a particularly favorable prognosis.

A diagnosis of alveolar rhabdomyosarcoma is made if the tumor has alveolar-like spaces that are filled with round malignant, eosinophilic cells. Presence of any amount of alveolar morphology in the lesion qualifies it to be alveolar rhabdomyosarcoma, and alveolar morphology has been identified as a poor prognosticator. There is also a solid variant of this tumor that lacks alveolar spaces but is still included in this subtype. The presence of sheets of anaplastic cells warrants a diagnosis of pleomorphic rhabdomyosarcoma. Today the diagnosis of the less favorable alveolar subtype is generally based on the identification of the characteristic chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36,q14) and their fusion products (see Table 63-1).²⁷

Both translocations may be associated with different clinical phenotypes.⁷⁵ The translocations and the gene fusion products are characteristic, and the PAX3 gene family involved in the disease fingerprint may have a role in muscle development.^76,77

Rhabdomyosarcoma is also one of the sarcomas associated with a risk of lymph node metastasis. Irrespective of age, the alveolar and embryonal subtypes manifest high rates of response to chemotherapy and RT. The initial evaluation of rhabdomyosarcoma is similar to regular STS but should ordinarily include bone marrow examination. Sampling of cerebrospinal fluid should be considered in patients with parameningeal lesions. Rarely, but distinctly, there is a tendency for these lesions to develop synchronous or metachronous metastases in one or both breasts (Fig. 63-2).

Figure 63-2 A, CT of the chest of a female patient presenting with a bilateral breast metastasis of an alveolar rhabdomyosarcoma arising in the left ethmoidal sinus. Note characteristic presentation with orbital invasion (B) and extensive cervical lymphadenopathy (C) shown by coronal MRI. Breast metastasis is not infrequent as a site of relapse in adult females with this disease but also may be seen at initial presentation.

Liposarcoma

Liposarcoma is the second most commonly encountered subtype of STS, and myxoid liposarcoma (MLS) is the most common variant.⁷⁸ Classic MLS has a t(12:16) translocation, resulting in the TLS-CHOP fusion shared with the more aggressive round cell variant and not seen in predominantly myxoid, well-differentiated liposarcoma.⁷⁹ It also has an unusual pattern of recurrence that includes a predilection for soft tissue metastases.^80–83,84

Apparent multifocal presentation or recurrence at two or more anatomically separate soft tissue sites (with predilection for the retroperitoneum and mediastinum) and bone metastases are a striking yet unpredictable feature of myxoid liposarcoma and contrasts to other STS (Fig. 63-3). Surgery and RT may result in relatively long disease-free intervals (e.g., many years). Uncertainty had existed about whether such multifocal lesions represent an unusual pattern of metastasis or multiple separate primary tumors until Antonescu and associates⁸⁵ showed that all cases of multifocal myxoid liposarcoma bore the identical molecular lineage of the parent primary tumor.

Figure 63-3 CT showing isolated mediastinal relapse with tracheal obstruction occurring in a patient who had presented 7 years previously with a myxoid liposarcoma in the popliteal fossa similar to the lesion shown in Figure 63-9. The initial limb lesion was treated with preoperative RT and maintained local control. This patient underwent airway management, preoperative RT, and surgical resection and was disease free with 15 months of follow-up. Isolated soft tissue relapse in this fashion is a hallmark of the behavior of myxoid liposarcoma and may result in long-term remission or salvage of such lesions.

More favorable survival in a large cohort of liposarcoma patients compared with other histologic subtypes has been reported in a series exceeding 1000 cases. The observation was independent of other prognostic factors, including grade, depth, and tumor size.⁸⁶ Myxoid liposarcoma also appears to manifest an unusually sensitive response to RT^87,88 (Fig. 63-4). Two theories, which are not mutually exclusive, of the underlying mechanism have been postulated. RT might cause adipocyte-like maturation/differentiation of tumor cells,⁸⁸

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