3. Epidemiology, risk factors and prevention – Soft Tissue Sarcoma

Internationally, incidences of soft tissue sarcomas are reported to range from 1.8 to 5.0 per 100,000 persons per year [11], [12]. Regional differences in incidence rates are based on differences in ethnic composition of the population, new Kaposi–sarcoma incidence rates, classification systems used, and diagnostic capabilities, among other factors.

Incidence estimates for soft tissue tumors from the Center for Cancer Registry Data at the Robert Koch Institute summarize tumors according to ICD-10 C46-C49. Thus, approximately 16% also include tumors that occur in these localizations but are not sarcomas. In addition, organ-specific sarcomas are not included in these registry codes, since, for example, sarcomas in the lung are coded with C34 in cancer registries, or the relatively frequent leiomyosarcomas and carcinosarcomas/Müllerian mixed tumors of women are coded with C54 [13]. Gastrointestinal stromal tumors as the most common sub-entity of soft tissue tumors are classified nonspecifically („unspecified“) as C15.9 (esophagus), C16.9 (stomach, C17.9 (duodenum, small intestine), C18.9 (colon), and C20.9 (rectum), and possibly also as C52 (spatium recto-vaginale), depending on the organ. For Germany, this underestimates the specific new case rate of soft tissue sarcomas when compared with routine reporting in some other countries.

In a specific analysis of Germany-wide cancer registry data (excluding Baden-Württemberg) for the diagnosis year 2013 with identification of sarcomas by histology and inclusion of all new cases of persons aged 15 years and older, including gastrointestinal stromal tumors (GIST)- 3,048 new cases were registered in men and 3,140 diagnoses of soft tissue sarcomas in women. This represents an incidence of 6.3 per 100,000 in men and 5.7 per 100,000 in women. The median age of onset was approximately 69 years in both sexes. For GIST, 1,353 cases were reported, corresponding to an age-standardized incidence of 1.5 per 100,000 men and 1.1 per 100,000 women [14].

Rhabdomyosarcomas and synovial sarcomas account for approximately one-third of soft tissue sarcoma diagnoses in young adults [15]. In contrast, the most common diagnoses in older adults are sarcomas with undifferentiated histology, complex neoplasms, leiomyosarcomas, liposarcomas, fibrosarcomas, and pleomorphic sarcomas [14], [16]. Table 6 shows the breakdown by histological subtype in the pooled data set of the German cancer registries for the diagnosis year 2013 [14].

Data on mortality and death rates of patients with soft tissue tumors in Germany have the same limitation as the incidence estimate in routine health reporting: a presentation is made summarized according to ICD-10 C46-C49 as a group of soft tissue including Kaposi's sarcoma (C46) and malignant neoplasms of the peripheral nerves and autonomic nervous system (C47). For 2015, the cause-of-death statistics of the Federal Statistical Office for Germany document a total of 1,770 deaths for this group (men 843, women 927). The age-standardized mortality rate was thus 1.4 per 100,000 for men and 1.3 per 100,000 for women.

For C46-C49 in 2013 and 2014, the Center for Cancer Registry Data reports relative 5-year survival rates of 64 % for men and 49 % for women. The absolute 5-year survival rates are correspondingly slightly lower at 55 % (men) and 44 % (women) [13]. For Europe as a whole, the RARECARE project reported 5-year relative survival for soft tissue sarcomas to be 58 % on average. The survival rates of individual soft tissue sarcomas vary. Sarcomas of the skin (mainly dermatofibrosarcoma protuberans) range from 90 % and higher, while soft tissue sarcomas of the mediastinum or heart have survival rates below 15 % [12]. In addition to the histological subtype, the degree of differentiation is decisive for the prognosis [17], [22].

Background

An increased risk of soft tissue sarcoma has been documented in people with immune deficiency. A survey by the U.S. Centers for Disease Control (CDC) showed that between 1983 and 1986, Kaposi's sarcoma rates in HIV patients ranged from 14.2% to 30.9% [23]. In addition, a systematic literature search revealed 176 cases of published non-Kaposi soft tissue sarcomas in immunosuppressed patients; 75 cases were diagnosed in HIV/AIDS patients and 101 cases in transplant patients. Soft tissue sarcoma diagnoses included leiomyosarcomas (n=101), angiosarcomas (n=23) and fibrohistiocytic tumors (n=17), rhabdomyosarcomas (n=8), GISTs (n=6), liposarcomas (n=4), Interdigitating dendritic cell sarcomas (n=3), fibrosarcomas (n=3), nerve sheath tumors (n=2), Ewing sarcomas (n=2), synovial sarcomas (n=1), osteosarcomas (n=1), carcinosarcomas (n=1), and other sarcomas (n=4)  [24].

The development of soft tissue sarcomas in immunosuppressed patients has been causally associated with viral infections. Human herpes virus 8 can be detected in > 90 % of all Kaposi's sarcomas, regardless of whether the affected individuals have HIV or are immunosuppressed [25], [26].

Furthermore, 85-88 % of leiomyomas and leiomyosarcomas diagnosed in immunocompromised patients contain Epstein Barr virus (EBV) [24], [27], whereas leiomyomas and leiomyosarcomas in immunocompetent patients are EBV negative [28]. The incidence of leiomyosarcoma in the general population is 0.81–1.23 cases per year per 100,000 people [11]. The incidence of EBV-associated soft tissue tumors after solid organ transplantation is reported to be 0.7 per 1000 patient-years [29]. After heart transplantation in childhood, the incidence is 2.6 per 1000 patient-years [29]. Numerous case reports also demonstrate that individuals with congenital cellular immunodeficiencies are at increased risk of developing EBV-associated soft tissue tumors [27], [30], [31]. Causal treatment of the immunodeficiency is often associated with spontaneous remission of EBV-associated soft tissue tumors.

Background

There is an increased risk of developing soft tissue sarcoma after radiotherapy. Rubino et al followed 6,597 patients with breast cancer for an average of 8.3 years and identified 14 sarcomas (4 angiosarcomas, 4 malignant fibrous histiocytomas, 5 fibrosarcomas, and 1 osteosarcoma) in a retrospective case-control study. Each patient who developed a secondary sarcoma was matched with 7 other patients from the total cohort and compared with the incidence of sarcomas in the French general population. The study found a 7-fold increased risk of sarcoma for the former breast cancer patients. The sarcomas all occurred in or in close proximity to the former radiation field. All 14 sarcomas developed in sites that had received at least 11.8 Gy. There was a significant correlation between dose and effect (p< 0.001) [32]. Virtanen et al. used the Finnish Cancer Registry to study the sarcoma risk of 295,712 cancer patients. Sarcoma risk within 10 years of diagnosis was 3.2-fold increased after radiotherapy, 4.9-fold increased after chemotherapy, and 3.4-fold increased after radiotherapy and chemotherapy. Sarcoma risk after radiotherapy was higher for patients younger than 55 years [33].

Menu-Branthomme et al followed 4,400 patients from France and the United Kingdom with childhood solid tumors for an average of 15 years and identified 16 soft tissue sarcomas in a retrospective case-control study. Each patient who developed a secondary sarcoma was matched with 5 other patients from the overall cohort and compared with the incidence of sarcomas in the Danish cancer registry. The Danish registry was chosen because French cancer registries did not cover the relevant time period and other European cancer registries were too small for patients younger than 45 years. Soft tissue sarcoma risk was 19-fold increased after radiotherapy, 28-fold increased after chemotherapy, and 113-fold increased after radiotherapy and chemotherapy [34]. A British study showed that the risk of developing soft tissue sarcoma was increased 38-fold after radiotherapy with a dose > 30Gy in childhood [35].

When sarcomas occur as secondary malignancies after prior tumor treatment, the presence of tumor predisposition should always be considered. Patients with cancer predisposing germline defects are more likely to develop secondary malignancies [36] (see Chapter 3.3).

Chronic lymphedema of the extremities, for example after therapy for breast carcinoma, is associated with the occurrence of secondary cutaneous angiosarcomas (Stewart-Treves syndrome) [37], [38].

The X-ray contrast agent Thorotrast was used for angiographic studies in Europe, Japan, and the United States from 1930 to 1960. An estimated 100,000 people were exposed. Thorotrast was first associated with angiosarcomas of the liver in 1947. There is also an association with cholangiocarcinomas and hepatocellular carcinomas. Tumors occur between 16 and over 45 years of age after thorotrast exposure [39]. In 2014, a case was published in which hepatic angiosarcoma occurred 65 years after thorotrast exposure [40].

Occupational exposures associated with increased soft tissue sarcoma risk have been investigated in several population studies. The Nordic Occupational Cancer (NOCCA) Project in Scandinavia showed a slightly increased soft tissue sarcoma risk among men for janitors (SIR  1.30, 95%, CI 1.08-1.56) and military personnel (SIR 1.27, 95% CI 1.01 - 1.59) [41]. In the US Selected Cancers Study, there was some correlation between soft tissue sarcoma incidence and contact with chlorophenol (adjusted OR 1.79, 95 % CI 1.10 – 2.88) and cutting oils (adjusted OR 1.65, 95 % CI 1.04 – 2.61) [42]. The association between occupational exposure to vinyl chloride and the occurrence of angiosarcoma of the liver is considered established [43].

Published studies regarding a possible association between alcohol or tobacco use and the occurrence of soft tissue sarcomas yielded conflicting results, so that ultimately no conclusion can be drawn [44], [45].

No association was observed between differences in birth weight, growth/development in adolescence, age at menopause, number of births and incidence of soft tissue sarcomas [10].

Background

Li-Fraumeni syndrome is a hereditary tumor predisposition syndrome caused by a germline mutation in the TP53 gene in at least 70 % of cases [47], [48]. CDKN2A germline mutations were found in 8 of 667 families with Li-Fraumeni like syndrome [46].

Soft tissue sarcomas occur in 12-21% of people with Li-Fraumeni syndrome [48], and account for 15%-25% of all cancers associated with Li-Fraumeni syndrome [47], [49], [50]. Soft tissue sarcomas associated with Li-Fraumeni syndrome occur at a younger age than sporadic soft tissue sarcomas [49]. In a study of 475 tumors in 91 families with TP53 germline mutations, rhabdomyosarcomas (55 %), fibrosarcomas (13 %), and undifferentiated pleomorphic sarcomas (10 %) were shown to be the most common soft tissue sarcomas associated with a TP53 germline mutation [51].

In rhabdomyosarcomas, TP53 germline mutations are found in 1-4% of all affected individuals [52], [53]. In rhabdomyosarcomas with a diagnosis age less than 3 years, the TP53 germline mutation rate increases to 23% [54]. In children with anaplastic rhabdomyosarcomas, the frequency of TP53 germline mutations is 73 % [55].

Familial polyposis adenomatosis coli (FAP) is an autosomal dominant hereditary cancer predisposition syndrome caused by germline mutations in the APC gene. Familial polyposis adenomatosis coli predisposes affected individuals to early formation of colorectal polyps, which typically develop into colon carcinomas by age 25 to 40 years.

Gardner syndrome is an FAP variant characterized by extracolonic manifestations [48]. This includes the development of desmoid fibromatosis in 7.5-16% of affected individuals [48]. In case series, FAP germline mutations have been found in people with desmoid fibromatoses in 0-16% of affected individuals. The germline mutation rate in children with desmoids was 16% [56], [57], [58].

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is the most common known tumor predisposition syndrome with an incidence of 1/3000 live births. A positive family history is present in approximately 50 % of cases. The clinical diagnosis of NF1 is made when two of the following seven criteria are met: (1) ≥ 6 café au lait spots of the skin (at least 5 mm in diameter in prepubertal and at least 15 mm in diameter in postpubertal individuals), (2) ≥ 2 neurofibromas or a plexiform neurofibroma, (3) freckling in the axilla or groin, (4) ≥ 2 Lisch nodules (iris hamartomas), (5) diagnosis of optic glioma, (6) dysplasia of the long bones with or without pseudarthrosis, (7) neurofibromatosis in a first-degree relative. NF1 is caused by loss-of-function mutations in the NF1 gene that lead to activation of the MAPK pathway.

People with NF1 have an 8-13% risk of developing a malignant peripheral nerve sheath tumor [59], [60], [61] and a 7% risk of developing a GIST during their lifetime [59]. There is also an increased risk of rhabdomyosarcoma [62].

Carney-Stratakis syndrome is an autosomal dominant hereditary tumor predisposition syndrome associated with gastrointestinal stromal tumors (GIST) and paragangliomas. Carney-Stratakis syndrome is caused by germline mutations in the SDH gene subunits (SDHA, SDHB, SDHC, SDHD) [48], [63]. Boikos et al identified SDHX germline mutations in 31 people with wild-type (WT) GIST. The associated tumors did not carry KIT or PDGFRA mutations, and SDHB expression was undetectable by immunohistochemistry [64], [65]. A proportion of WT GISTs were associated with neurofibromatosis type 1 [63], [66].

KIT-mutated GISTs can occur in people with KIT germline mutations, associated with dysphagia with or without hyperpigmentation and various manifestations of mastocytosis [63]. PDGFRA-mutated GISTs may occur in people with PDGFRA germline mutations, associated with lipomas, intestinal fibromas, and large hands [63].

People who had hereditary retinoblastoma as children are more likely to develop soft tissue sarcomas. Soft tissue sarcomas occur both in the former radiation field and outside the radiation field 67, reaching a 60-year incidence of 9.3% (95% CI 7.0-11.7%) in the head and neck region. In contrast, sarcomas of the extremities do not cluster after adolescence  [67]. In 7 of 525 women with hereditary retinoblastomas, uterine leiomyosarcomas were diagnosed later [68].

Finally, in case series, the following soft tissue sarcoma histotypes were associated with germline mutations in specific cancer-related genes: DICER1 germline mutations were found in 4 of 9 patients with anaplastic renal sarcomas [69]; the latter were also detected in patients with embryonal rhabdomyosarcoma of the cervix [70]. Germline mutations in the TBXT gene (brachyuria) were identified in 4 families with chordomas [71].

In addition to Li-Fraumeni syndrome, Dicer1 syndrome and neurofibromatosis type 1, embryonal rhabdomyosarcomas are associated in rare cases with Bloom syndrome, mismatch repair deficiency syndrome, Costello syndrome (HRAS germline mutations), Gorlin syndrome (PTCH1), Nijmegen breakage syndrome, Noonan syndrome (PTPN11), Rubinstein Taybi syndrome and Werner syndrome [59], [72], [73].

Angiomyolipomas and PEComas occur in people with tuberous sclerosis and are associated with TSC1 or TSC2 germline mutations [59].

Background

The desire of women and men for detailed information and shared decision-making about prevention and treatment options has been repeatedly documented. In a survey of 1200 participants in the International Sarcoma Kindred Study (ISKS), 60% of soft tissue sarcoma patients interviewed reported a positive attitude toward genetic diagnosis to detect hereditary predispositions [75].

The results of the case-control study showed that 638 patients (55%) had a significantly increased rate of pathologic germline abnormalities (OR 1·43, 95% CI 1·24–1·64, p<0·0001) [76]. All pathogenic variants were associated with earlier onset of cancer. In addition to the known TP53, ATM, ATR, and BRCA2 alterations, pathogenic variants of ERCC2 were also found with disproportionate frequency. These findings have implications for risk management as well as current treatment.

Consensus-based recommendation 3.7. was adapted from recommendations 3.31. and 3.32. of the S3 guideline Breast Cancer.

Background

Prospective studies have shown that the use of a screening program in TP53 germline mutation carriers in childhood and adulthood, including annual whole-body MRI examinations, resulted in early detection of tumors and improved survival in 40 affected individuals (89% at 5 years, compared with 60 % in the control group) [77], [78]. In another study, baseline whole-body MRI was performed in 578 TP53 germline mutation carriers; 42 malignancies were found in 39 affected individuals, of whom 35 were treated with curative intent [79]. The Toronto Protocol provides for the following screenings:

 

For children, adolescents, and adults:

• Complete physical examination every four months, including blood pressure, neurological examination, and for children, growth and pubertal signs.
• Laboratory tests every four months: BB/diff, LDH, ESR, 17-OH-progesterone, testosterone, DHEA-S, androstenedione.
• Cortisol level in 24h collection urine every four months.
• Ultrasound of abdomen and pelvis every four months.
• Cranial MRI once a year.
• Whole body MRI once a year.

 

Additionally, for adults over 18 years of age:

• Women: Breast self-exam once a month, physician breast exam every six months, breast MRI once a year starting at age 20-25 or 5-10 years before earliest family diagnosis of breast cancer.
• Colonoscopy/gastroscopy every 2-5 years starting at age 25, or 10 years prior to first colon cancer in family.
• Dermatological examination once a year.