Soft-Tissue Sarcoma

Environmental Factors

The majority of STS develop without having clear predisposing factors. In some patients environmental, immunologic, and familial factors have been reported. Among environmental factors, exposure to radiation is one of the most commonly cited risk factors. The incidence of radiation-associated STS is not well established because, in part, of a long latency period. The estimate is that it develops in less than 1% of patients who received radiation therapy, but account for about 5% of soft-tissue sarcomas. The most common histologies are angiosarcoma and unclassified sarcoma. Less-common histologies include malignant peripheral nerve sheath tumors (MPNST), leiomyosarcoma, and osteosarcoma. The exact mechanism of radiation-associated sarcomas is not clear. It is possible that the genetic defect that may have led to the development of the first cancer for which RT was administered, may in turn, have led to the induction of the RT-associated sarcoma. The most common site for radiation-associated sarcomas is the breast. In a meta-analyses of women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials, there were 23 cases of secondary sarcomas of 194,957 patients who received radiation as opposed to 17 of 180,250 who did not. This yielded a rate ratio of 1.36 (0.71 to 2.59), p = 0.36. The prognosis of RT-associated STS is worse than sporadic STS independent of histologic type. However within RT-associated STS, histology, such as angiosarcoma of the breast, seems to impart a better prognosis.

The exposure to chemical carcinogens, including Thorotrast, vinyl chloride, and arsenic, have been linked to hepatic angiosarcomas. There have been conflicting reports about occupational exposure to phenoxyherbicides, chlorophenols, and dioxins and the increase in risk of developing STS. Trauma is not considered a risk factor for STS; often a minor trauma draws the attention to the lesions. The question of whether the trauma from orthopedic surgery may increase the risk of sarcoma was addressed in a study from the Finnish Arthroplasty Register. A cohort of 24,636 patients with primary osteoarthritis and metal-on-polyethylene total hip arthroplasty who had been entered in the Finnish Arthroplasty Register were assessed for cancer risk. The mean follow-up time was 13 years. The numbers of cancer cases observed were comparable to the incidence in the general population.

Immunologic Factors

Systemic or regional immunologic factors have been linked to STS. For systemic factors, HIV-related Kaposi's sarcoma, which is linked to human herpes virus 8, is well documented. Patients who are immunosuppressed, such as patients who have undergone transplants, are also at increased risk of smooth muscle tumors that are linked to Epstein-Barr virus. Chronic lymphedema, which could be considered a regional immunodeficiency phenomenon (Stewart-Treves syndrome), has been implicated in the development of lymphangiosarcoma in patients with breast cancer treated with radical mastectomies and axillary lymph node dissection. It is important to note that this sarcoma is not directly linked to radiation exposure because some of these patients did not have radiation; for those who did, many developed their lymphangiosarcoma outside the radiation field.

Hereditary Factors

Soft-tissue sarcomas are occasionally associated with inherited genetic conditions. Neurofibromatosis type I is an autosomal-dominant disorder with deletion or loss of function of NF1 on chromosome 17. The product of NF1 is neurofibromin, which generally suppresses RAS activity. The risk of developing a malignant peripheral nerve sheath tumor in these patients is about 10% over a lifetime. Li-Fraumeni syndrome is another autosomal-dominant hereditary cancer syndrome with a spectrum of tumors including breast cancer (most common), sarcomas (second-most common), leukemia, brain tumors, and adrenocortical carcinomas. The underlying abnormality is germline deletion of the p53 suppressor gene. The function of p53 is to guard the integrity of the genome against DNA-damaging agents or hypoxia. When normal p53 is activated, it leads to cell cycle arrest at G1 and induction of DNA repair. Gardner syndrome, a subset of familial adenomatous polyposis, is associated with the development of intraabdominal desmoids. In these patients there is loss of expression of the adenomatous polyposis coli (APC) gene.

Sarcomas with Complex Genetic Alterations

The majority of STS belong to this group. In a recent report, The Cancer Genome Atlas (TCGA) performed multi-platform molecular landscape analysis on 206 adult soft-tissue sarcomas. There were five major adult STSs with complex karyotypes: undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), and malignant peripheral nerve sheath tumor (MPNST). These histologies were compared with a simple-karyotype sarcoma, synovial sarcoma (SS). The analysis revealed three general features for the sarcomas with complex karyotypes. First, high prevalence of somatic copy number alterations as opposed to activating point mutations with deletions being more prominent than amplifications (less so in DDLPS). Second, only a few genes ( TP53, ATRX, RB1 ) were highly recurrently mutated with more mutations in tumor suppressor genes than in oncogenes. Third, low somatic mutational burdens ( Fig. 75.1 ). But the analyses also revealed distinct differences among these histologies with complex karyotype. For example: MDM2, CDK4, JUN , and TERT amplifications in DDLPS; MYOCD amplification, PTEN mutations/deletions, and AKT, IGF1R, and MTOR pathway activation in LMS; and VGLL3 amplification and Hippo pathway activation in UPS/MFS. Furthermore, genomic analyses identified prognostically distinct subsets within DDLPS and within nongynecologic LMS that could augment risk stratification and guide new therapeutic interventions. Despite the low mutational burdens, immune cell infiltration in the tumor microenvironment was commonly detected in genomically complex DDLPS, LMS, UPS, and MFS and was highly associated with clinical outcome.

Pathology Classification

Pathologic classification of STS is challenging. There are about 50 histologic types of STS. Traditional approaches relied heavily on trying to match the morphology of STS with what is thought to be the soft tissue of origin of the sarcoma. Such an approach has its limitations, for example, synovial sarcomas do not arise from the synovium per se . Malignant fibrous histiocytoma (MFH), previously considered one of the most common histologies, was thought to derive from histiocytes. Not only was that derivation unfounded, the term MFH itself is questionable because on reexamination many of these tumors could be classified along other lineages.

The current emphasis in pathologic classification of STS is more on the line of differentiation of the tumor, such as adipocytic (e.g., liposarcomas), fibroblastic and myofibroblastic (myxofibrosarcoma), smooth muscles (leiomyosarcoma), skeletal muscles (rhabdomyosarcomas), nerve sheath (malignant nerve sheath tumors), undifferentiated (undifferentiated pleomorphic sarcoma), and uncertain differentiation (synovial sarcoma). Light microscopic examination plays a significant role in assigning histologic type and grade.

Grading of STS is critical; in fact, the staging system is primarily driven by it. Several grading systems are in use: at MSKCC a two-tier system is used (high versus low), the American Joint Committee on Cancer (AJCC) staging system uses a three-tier system (grades 1, 2, and 3). Irrespective of the system, grade is highly predictive of outcome, in terms of LR, distant spread, and survival. These different grading systems rely, to a varying degree, on tumor differentiation, mitosis, degree of necrosis, and histologic subtypes. No grading system is perfect; at MSKCC the two-tier system is preferred because of its simplicity. Low grade is equivalent to grade 1 in the three-tier system, and high grade is equivalent to grade 2 or 3.

In addition to morphology, there has been a great emphasis on using immunohistochemistry to better assign a line of differentiation. Some of the common markers used to determine the line of differentiation include desmin, vimentin, cytokeratin, and S-100, to name a few. Newer markers are being used to detect specific molecular aberrations such as MDM2/CDK4 amplification in well-differentiated and dedifferentiated liposarcomas to separate them from benign lipomatous tumors. Perhaps the biggest improvement in STS classification has been through molecular testing . For example, signature translocations such as t(X; 18) is diagnostic for synovial sarcomas. STS rank second to hematological malignancies in the number of signature translocations (see Table 75.1 ). The molecular tests used to detect a translocation generally include reverse transcriptase-polymerase chain reaction (RT-PCR), and fluorescence in situ hybridization (FISH). The 2013 World Health Organization (WHO) classification of soft-tissue tumors relies on morphology, immunohistochemistry, and genetic features ( Box 75.1 ).

Selected Pathologic Subtypes

Liposarcoma

Liposarcoma is the most common histology when all sites are considered. In the 2013 WHO classification, there are four subtypes of liposarcoma: myxoid, dedifferentiated, pleomorphic, and not otherwise specified. Atypical lipomatous tumor and well-differentiated liposarcoma are considered intermediate (locally aggressive) in the WHO classification. Most well-differentiated liposarcomas (WDL ) occur in the fifth to seventh decades of life. Extremity is the most common location (about 75%) followed by retroperitoneum. These low-grade tumors tend to have an indolent course with low risk for distant recurrence irrespective of site. Extremity WDL can recur locally, but the risk is relatively low to justify routine use of adjuvant RT, especially in the primary setting. In contrast, a WDL in the retroperitoneum tends to recur often.

Myxoid liposarcoma has a signature translocation at t(12 : 16) in 90% of cases and t(12;22) in less than 5%. They are predominantly seen in extremity sites (most common liposarcoma in extremity) and affect younger patients usually in the third to fourth decades of life. The term round cell is no longer used in association with myxoid liposarcoma based on the 2013 WHO classification; these tumors are graded to reflect the spectrum of their behavior. Recognizing myxoid liposarcoma has significant clinical implications for radiation oncologists because these tumors are exquisitely radiosensitive ( Fig. 75.2 ). In addition, they tend to metastasize to unusual sites for STS, such as the spine.

Dedifferentiated liposarcomas are often seen in the retroperitoneum (75%), but other sites include spermatic cord, trunk, and head and neck. It commonly affects older patients and, on imaging, the tumors can have a mixture of solid masses (similar to other STS), mixed with areas of “fatty-looking” tissues. Microscopically this is represented by a mixture of WDL and dedifferentiated liposarcomas.

Pleomorphic liposarcomas are the least common liposarcomas. They can arise in an extremity or the retroperitoneum. They are high-grade lesions with aggressive behavior. At MSKCC, a nomogram has been developed to predict the outcome of liposarcoma across different sites.