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Childhood Soft Tissue Sarcoma

Childhood soft tissue sarcomas (STS) constitute a heterogeneous group of mesenchymal malignancies. Rhabdomyosarcoma, particularly embryonal rhabdomyosarcoma, accounts for the majority of cases. Non-rhabdomyosarcoma STS comprise more than 50 entities, all of which are rare.


Presentation

Childhood STS may develop anywhere in the body, so the clinical presentation of these malignancies is highly variable. While rhabdomyosarcomas most frequently affect the head and neck region, the genitourinary system, and the limbs, non-rhabdomyosarcoma STS are usually detected in the extremities [1] [2].

Patients may present with visible or palpable mass lesions, or symptoms of mass effects are observed. Tumors affecting the head may cause cranial nerve palsy with sensory and motor deficits, hearing loss and visual impairment, proptosis, dysphagia, and dyspnea. Deformities may be noted, and affected children may suffer from pain. Neoplasms developing in the abdominal cavity or genitourinary tract may interfere with the intestinal transit or the collection and excretion of urine. The invasion of the respective hollow organs may result in melena, hematochezia, or hematuria.

Constitutional symptoms such as fever, night sweats, and unintentional weight loss are rare [3].

Constitutional Symptom
  • Constitutional symptoms such as fever, night sweats, and unintentional weight loss are rare. Clinical findings may or may not allow for a tentative diagnosis of childhood STS.[symptoma.com]
Fishing
  • Related: Bone Cancers FISH FOXO1A MYOG Williams RF, Fernandez-Pineda I, Gosain A Pediatric Sarcomas.[cancerindex.org]
Splenectomy
  • Because of the rapid onset of thrombocytopenia and anemia, the patient required urgent splenectomy with subsequent resolution of the blood dyscrasias. Related: Kaposi Sarcoma Collini P, Barisella M, Renne SL, et al.[cancerindex.org]
Hematochezia
  • The invasion of the respective hollow organs may result in melena, hematochezia, or hematuria. Constitutional symptoms such as fever, night sweats, and unintentional weight loss are rare.[symptoma.com]
Melena
  • The invasion of the respective hollow organs may result in melena, hematochezia, or hematuria. Constitutional symptoms such as fever, night sweats, and unintentional weight loss are rare.[symptoma.com]
Dysphagia
  • Tumors affecting the head may cause cranial nerve palsy with sensory and motor deficits, hearing loss and visual impairment, proptosis, dysphagia, and dyspnea. Deformities may be noted, and affected children may suffer from pain.[symptoma.com]
Night Sweats
  • Common Symptoms A solid lump or mass, usually in the trunk, arms or legs Other symptoms depend upon the location of the tumor and if it is interfering with other bodily functions Rarely causes fever, weight loss or night sweats If your child has any of[urmc.rochester.edu]
  • Constitutional symptoms such as fever, night sweats, and unintentional weight loss are rare. Clinical findings may or may not allow for a tentative diagnosis of childhood STS.[symptoma.com]
  • Soft tissue sarcoma rarely causes fever, weight loss, or night sweats.[stanfordchildrens.org]
Visual Impairment
  • Tumors affecting the head may cause cranial nerve palsy with sensory and motor deficits, hearing loss and visual impairment, proptosis, dysphagia, and dyspnea. Deformities may be noted, and affected children may suffer from pain.[symptoma.com]
Suggestibility
  • The findings confirm an association among childhood soft tissue sarcoma and cancers of the breast, bone, joint, or soft tissue as SMN in patients and in close relatives and suggest that the risk of a second tumor is associated with a familial predisposition[ncbi.nlm.nih.gov]
  • Adjuvant chemotherapy plus radiation is suggested for patients who underwent surgery for metastatic disease. Of note, "small" and "large" generally refer to tumors measuring more or less than 5 cm in diameter.[symptoma.com]
  • These results suggest that new agents found effective in adult patients might achieve similar results in adolescents with the same disease.[cancerindex.org]
Perseveration
  • Perseverance during rhabdomyosarcoma treatment After the diagnosis, Dr. Lin consulted Winston W. Huh, M.D., at MD Anderson Children’s Cancer Hospital. “We love Dr. Huh,” Hadley says. “He has kids, so he gets it. He really gets down on their level.[mdanderson.org]
Excitement
  • He’s also excited that he can finally eat sushi again. “When they told Kobee he could eat sushi again, he pigged out,” Hadley recalls.[mdanderson.org]

Workup

Clinical findings may or may not allow for a tentative diagnosis of childhood STS. In any case, tissue samples have to be obtained for the histopathological assessment of the neoplasm, its identification, and the determination of tumor grade. A core-needle biopsy, incisional biopsy, or excisional biopsy may be carried out to this end. Furthermore, diagnostic imaging should be employed to define the localization and extension of the tumor, and to clarify whether metastases have formed.

Most STS can be diagnosed with confidence using conventional light microscopy. One of the key characteristics of STS is the morphology of the tumor cells, which may be round, spindle-shaped, or epitheliod. The histological identification of the tumor may be hampered, though, if it is poorly differentiated and/or combines the features of distinct types of STS [4]. These cases may require an extensive immunohistochemical and possibly molecular characterization.

Embryonal rhabdomyosarcoma is composed of sheets of rhabdomyoblasts with dense but irregularly distributed chromatin. The alveolar type, however, is reminiscent of the alveoli of the lung. Its rhabdomyoblasts are organized in clusters where centrally located cells tend to die, leaving "empty" spaces behind. The rhabdomyoblasts of alveolar rhabdomyosarcoma are less well differentiated than those cells composing embryonal rhabdomyosarcoma. Large, lobulated, and hyperchromatic nuclei as well as atypical mitoses are characteristic of undifferentiated, pleomorphic rhabdomyosarcoma. There may be focal anaplasia in embryonal and alveolar rhabdomyosarcoma, which adversely affects the prognosis [5]. Spindle-cell/sclerosing rhabdomyosarcoma has been defined as a fourth type of rhabdomyosarcoma in the "Classification of Tumours of Soft Tissue and Bone" as published by the World Health Organization [6]. Here, spindle-shaped or round tumor cells are embedded in a dense, hyalinizing collagenous matrix. With regards to non-rhabdomyosarcoma STS, Spunt and colleagues have published a list of the key features of the most common tumor types [7].

With regard to tumor staging, computed tomography and magnetic resonance imaging are most commonly utilized. Positron emission tomography may also be carried out and has been proven a sensitive technique to identify distant metastatic disease [3] [8]. Primary tumors arising in the head and neck region preferentially metastasize to the lungs, while malignancies emerging in the abdominal cavity tend to metastasize to the peritoneum or liver. Regional metastases may develop in the respective lymph nodes beforehand [9]. According to epidemiological and surveillance data, about half of childhood STS are diagnosed in early stages, in the absence of regional and distant metastases [3].

Treatment

Due to the rarity of non-rhabdomyosarcoma childhood STS, data regarding the efficacy and tolerability of certain treatment regimens are scarce. Accordingly, expertise gained in adult patients is often extrapolated to the pediatric population [9]. A comprehensive standard of care to guide clinical decision making in rhabdomyosarcoma patients is also lacking, but clinical trials involving the pediatric age group have been carried out [8]. In general, affected children benefit from a multidisciplinary approach to therapy [3] [8] [9]:

  • The surgical removal of the neoplasm may be curative if clean margins can be obtained. This is the best course of action in case of small and low-grade STS.
  • (Neo-)adjuvant radiotherapy is indicated for large or high-grade STS and to avoid recurrences from positive margins, while adjuvant chemotherapy is recommended for grossly removed, large and high-grade STS, irrespective of the presence of tumor cells in surgical margins. Furthermore, given the high rate of micrometastatic disease leading to relapses in patients treated only with local therapy, all children diagnosed with rhabdomyosarcoma should additionally be treated with chemotherapeutics.
  • Neoadjuvant chemoradiotherapy may prepare patients with as-of-yet unresectable tumors for surgery. Adjuvant chemotherapy plus radiation is suggested for patients who underwent surgery for metastatic disease.

Of note, "small" and "large" generally refer to tumors measuring more or less than 5 cm in diameter. The threshold may vary, though, depending on the age of the child [3].

Prognosis

The site and size of the primary tumor (and any metastasis), the depth of invasion, the presence of metastases, histological findings and tumor grade, as well as the resectability of the tumor are important prognostic factors [3]. In most cases, pediatric STS patients have a favorable prognosis. According to epidemiological data obtained in the United States, the five-year survival rate exceeded 70% in the decades 1975-1984 and 1985-1994 [1].

Etiology

STS is a general term that may refer to distinct types of malignant neoplasms. In pediatric patients, up to 60% of STS are rhabdomyosarcomas, which originate from skeletal muscle tissue. There are four types of rhabdomyosarcoma, namely embryonal, alveolar, pleomorphic, and spindle-cell/sclerosing rhabdomyosarcoma, with embryonal rhabdomyosarcoma being the most common one.

The remainder of childhood STS is sometimes referred to as non-rhabdomyosarcoma STS and includes several dozen entities, each one of which is rare [7]. A practical way to classify these types of STS is according to the morphology of the predominant cell type. In this context, the following types of malignancies shall be mentioned by way of examples [1] [6] [7]:

This scheme shall provide orientation, but the assignment to a certain group is not irrevocable. There may be tumors displaying features of more than one group, as is the case with extraskeletal myxoid chondrosarcoma [10]. Other classification systems, like the one published by the World Health Organization, is based on the tissues of origin. Here, adipocytic tumors, fibroblastic/myofibroblastic and fibrohistiocytic neoplasms, smooth-muscle and skeletal-muscle tumors, nerve sheath tumors and STS of uncertain differentiation are described [6].

The vast majority of childhood STS occurs sporadically. Few cases are related to congenital cancer susceptibility, e.g., owing to Li-Fraumeni syndrome, neurofibromatosis type 1, familial adenomatous polyposis, or Werner syndrome [1] [3].

Epidemiology

STS account for about 8% of all neoplasms in childhood and adolescence, with almost equal proportions of rhabdomyosarcoma and non-rhabdomyosarcoma STS [2]. For the United States and the period from 1975 to 1995, the age-specific incidence of STS has been estimated at 11 per 1,000,000 people aged <20 years. The largest shares by far arise from rhabdomyosarcoma and fibrosarcoma-like neoplasms as described in the previous paragraph (age-specific incidence rates of 4.3 and 3.2 per 1,000,000, respectively) [1]. Similar numbers have been reported in Germany [4].

Epidemiological data indicate a slight predisposition of males and black children, although gender and racial differences may vary between distinct types of STS [1]. As a rule of thumb, rhabdomyosarcomas are more likely to develop in very young patients, while non-rhabdomyosarcoma STS are more commonly diagnosed in older children and adolescents [2].

Sex distribution
Age distribution

Pathophysiology

Childhood STS are of mesenchymal origin, and mesenchymal cells physiologically differentiate into skeletal muscle, smooth muscle, fat, fibrous tissue, bone and cartilage [1]. Besides a genetic predisposition, the exposure to certain environmental factors may cause these cells to degenerate and to accumulate chromosomal aberrations and altered gene expression. Certain chemotherapeutic agents, ionizing radiation, and parental recreational drug use are among the environmental triggers involved in the development of STS [5]. Further, as-of-yet unknown factors presumably adds to the process, thereby giving rise to the development of malignancies with a determined molecular signature. Hyperdiploidy and loss of heterozygosity, for instance, are characteristic of embryonal rhabdomyosarcoma, while translocations involving the FOXO1 gene on 13q14.11 with genes of the PAX family on chromosomes 2 or 1 are detected in about two-thirds of alveolar rhabdomyosarcoma [1]. Accordingly, such findings may support a tentative diagnosis of childhood STS, but they must be interpreted in context: It must be kept in mind that the remaining third of alveolar rhabdomyosarcoma displays neither t(2;13)(q35;q14) nor t(1;13)(p36;q14) [5], and that del11p15.5, the most common variant of chromosomal aberration and allele loss in embryonal rhabdomyosarcoma, has also been described in nephroblastoma and other neoplasms. Similar statements could be made with regards to other types of childhood STS.

Prevention

As implied in the previous paragraph, few environmental factors favoring the development of childhood STS have been identified, e.g., chemotherapeutic agents, ionizing radiation, and recreational drugs. Parents and children may thus be encouraged to avoid these factors, but this may not always be possible: There may be no alternatives to chemotherapy and/or radiation to treat primary cancers, even though they imply an increased risk of secondary cancers in survivors [11]. In this context, data suggesting elevated risks for STS, acute myeloid leukemia, cutaneous melanoma, as well as cancers of the oral cavity and pharynx, female breast, and bone should prompt the inclusion of cured childhood STS patients in long-term surveillance programs. Furthermore, any workup of childhood STS should include genetic tests for cancer predisposition syndromes.

Summary

STS is a general term referring to solid tumors of mesenchymal cell origin that display a wide variety of clinical and pathologic characteristics. STS can develop from muscle, fat, nerves, blood vessels, and distinct types of connective tissues. Sarcomas account for about 1% of adult cancer cases only, but for up to 15% of malignancies diagnosed in pediatrics [9]. In children, the most common type of STS is rhabdomyosarcoma. Due to the rarity of all the other entities, such as fibrohistiocytic tumors, synovial sarcoma, and neoplasms of the Ewing family of tumors, they are generally gathered under the term non-rhabdomyosarcoma STS.

This article shall give a general overview about rhabdomyosarcoma and non-rhabdomyosarcoma STS, but specific recommendations should be followed when diagnosing and treating a patient found to suffer from childhood STS. Therefor, the reader is referred to the respective articles available on this platform and in literature.

Patient Information

Soft tissue comprises muscles, ligaments, tendons, and synovial membranes, blood vessels, nerves, and fat, among others. These tissues are composed of distinct types of cells, many of which are of the same embryonic origin: They derive from the so-called mesenchyme. Malignant tumors arising from mesenchymal tissues are named sarcoma, and, accordingly, "soft tissue sarcoma" may refer to a wide variety of tumors. In children, rhabdomyosarcoma is the most common type of soft tissue sarcoma. It derives from skeletal muscle tissue. Other examples are fibrous histiocytoma, fibrosarcoma, and synovial sarcoma. In sum, there are more than 50 types of childhood soft tissue sarcoma.

These tumors may develop anywhere in the body, but most frequently affect the head and neck region, abdominal cavity, and limbs. Patients may present with a visible or palpable mass that may or may not be painful, or they may suffer from symptoms attributable to mass effects. The sarcoma may exert pressure on surrounding structures, such as cranial nerves, eyes, trachea, or digestive tract, and interfere with the function of the respective organs. Thus, the clinical picture doesn't usually allow for a reliable diagnosis of soft tissue sarcoma. Tissue samples have to be obtained and microscopically examined to this end. Furthermore, diagnostic imaging has to be employed to assess the site and size of the tumor as well as the spread of the disease throughout the body.

References

Article

  1. Ries LAG, Smith MA, Gurney JG, et al. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. National Cancer Institute; Bethesda, MD: 1999.
  2. Sambri A, Bianchi G, Cucurnia I, Gambarotti M, Donati DM. Pediatric soft tissue sarcoma of the limbs: clinical outcome of 97 patients. Eur J Orthop Surg Traumatol. 2018; 28(1):1-7.
  3. PDQ Pediatric Treatment Editorial Board. Childhood Soft Tissue Sarcoma Treatment (PDQ(R)): Health Professional Version. PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); 2002.
  4. Harms D. Soft tissue sarcomas in the Kiel Pediatric Tumor Registry. Curr Top Pathol. 1995; 89:31-45.
  5. O'Brien D, Jacob AG, Qualman SJ, Chandler DS. Advances in pediatric rhabdomyosarcoma characterization and disease model development. Histol Histopathol. 2012; 27(1):13-22.
  6. Fletcher C, Bridge J, Hogendoorn P, Mertens F., eds. World Health Organization classification of tumours of soft tissue and bone: pathology and genetics of tumours of soft tissue and bone. 4 ed. Lyon, France: IARC Press; 2013.
  7. Spunt SL, Skapek SX, Coffin CM. Pediatric nonrhabdomyosarcoma soft tissue sarcomas. Oncologist. 2008; 13(6):668-678.
  8. Borinstein SC, Steppan D, Hayashi M, et al. Consensus and controversies regarding the treatment of rhabdomyosarcoma. Pediatr Blood Cancer. 2018; 65(2).
  9. von Mehren M, Randall RL, Benjamin RS, et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018; 16(5):536-563.
  10. Hisaoka M, Hashimoto H. Extraskeletal myxoid chondrosarcoma: updated clinicopathological and molecular genetic characteristics. Pathol Int. 2005; 55(8):453-463.
  11. Cohen RJ, Curtis RE, Inskip PD, Fraumeni JF, Jr. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer. 2005; 103(11):2391-2396.

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Last updated: 2019-07-11 20:15