Rhabdomyosarcoma
Rhabdomyosarcoma | |
---|---|
post-auricular congenital alveolar rhabdomyosarcoma. | |
Specialty | Oncology |
Rhabdomyosarcoma (RMS) is a highly aggressive form of
The four subtypes are
It is generally considered to be a disease of childhood, as the vast majority of cases occur in those below the age of 18. It is commonly described as one of the small-blue-round-cell tumors of childhood due to its appearance on an H&E stain.[4] Despite being relatively rare, it accounts for approximately 40% of all recorded soft-tissue sarcomas.[5][6][7]
RMS can occur in any soft-tissue site in the body, but is primarily found in the head, neck, orbit, genitourinary tract, genitals, and extremities. No clear risk factors have been identified, but the disease has been associated with some congenital abnormalities.[5][8] Signs and symptoms vary according to tumor site, and prognosis is closely tied to the location of the primary tumor. Common sites of metastasis include the lungs, bone marrow, and bones.[9][10] There are many classification systems for RMS and a variety of defined histological types. Embryonal rhabdomyosarcoma is the most common type and comprises about 60% of cases.[11]
Outcomes vary considerably, with five-year survival rates between 35 and 95%, depending on the type of RMS involved, so clear diagnosis is critical for effective treatment and management.[11][12]
Treatment usually involves a combination of surgery, chemotherapy, and radiation. 60 to 70% of newly diagnosed patients with nonmetastatic disease can be cured using this combined approach to therapy. Despite aggressive multimodality treatment, less than 20% of patients with metastatic RMS are able to be cured of their disease.[13]
Types
Given the difficulty in diagnosing rhabdomyosarcoma, definitive classification of subtypes has proven difficult. As a result, classification systems vary by institute and organization. Rhabdomyosarcoma in the 2020 WHO classification, though, is listed as four histological subtypes: embryonal, alveolar, pleomorphic, and spindle-cell/sclerosing.[citation needed]
Embryonal
Embryonal rhabdomyosarcoma (ERMS) is the most common histological variant, comprising about 60–70% of childhood cases. It is most common in children birth to four years old, with a maximum reported incidence of four cases per million children. ERMS is characterized by spindle-shaped cells with a stromal-rich appearance, and the morphology is similar to the developing muscle cells of a 6- to 8-week-old embryo. Tumors often present in the head and neck, as well as the genitourinary tract.[citation needed]
Embryonal subtype
Botryoid rhabdomyosarcoma is almost always found in mucosal-lined organs, including the vagina, bladder, and nasopharynx (although presentation in the nasopharynx typically affects older children). It often presents in infants younger than a year old, as a round, grape-like mass on the affected organ. Histologically, cells of the botryoid variant are defined by a dense tumor layer under an epithelium (cambium layer).[14] This subtype has a good prognosis.[11][12]
Botryoid rhabdomyosarcoma is also sometimes present in adult women, found in the cervix or uterus.[15]
Alveolar
Alveolar rhabdomyosarcoma (ARMS) is the second-most common type. ARMS comprises around 20–25% of RMS-related tumors, and it is equally distributed among all age groups with an incidence of about one case per million people ages 0 to 19. For this reason, it is the most common form of RMS observed in young adults and teenagers, who are less prone to the embryonal variant. This type of RMS is characterized by densely packed, round cells that arrange around spaces similar in shape to pulmonary alveoli, although variants have been discovered without these characteristic alveolar spacings. ARMS tends to form more often in the extremities, trunk, and peritoneum. It is also typically more aggressive than ERMS.[12][14]
Pleomorphic
Spindle-cell/sclerosing
Spindle-cell/sclerosing rhabdomyosarcoma is an added subtype listed in the 2020
This subtype is very similar to that of
Multiple classification systems have been proposed for guiding management and treatment, and the most recent and widely used classification system is the "International Classification of Rhabdomyosarcoma" or ICR. It was created by the IRSG in 1995 after their series of four multi-institutional trials aimed at studying the presentation, histology, epidemiology, and treatment of RMS (IRSG I–IV).[11] The ICR system is based on prognostic indicators identified in IRSG I–IV. Pleomorphic rhabdomyosarcoma usually occurs in adults rather than children, and is therefore not included in this system.[citation needed]
Signs and symptoms
RMS can occur in almost any soft-tissue site in the body; the most common primary sites are genitourinary (24%), parameningeal (16%), extremity (19%), orbit (9%), other head and neck (10%), and miscellaneous other sites (22%).[14] RMS often presents as a mass, but signs and symptoms can vary widely depending on the site of the primary tumor. Genitourinary tumors may present with hematuria, urinary tract obstruction, and/or a scrotal or vaginal mass. Tumors that arise in the retroperitoneum and mediastinum can become quite large before producing signs and symptoms. Parameningeal tumors may present with cranial nerve dysfunction, symptoms of sinusitis, ear discharge, headaches, and facial pain. Orbital tumors often present with orbital swelling and proptosis. Extremity tumors generally present as a rapidly enlarging, firm mass in the relevant tissue. The cancer's prevalence in the head, face, and neck will often allow for earlier signs of the disease simply due to the obvious nature of tumors in these locations.[14] Despite the varying presentation and typically aggressive nature of the disease, RMS has the potential to be diagnosed and treated early. The fourth IRSG study found that 23% of patients were diagnosed in time for a complete resection of their cancer, and 15% had resection with only minimal remnants of the diseased cells.[20]
Risk factors
Rhabdomyosarcoma is difficult to diagnose. Risk factors that increase the likelihood of this cancer include inherited disorders such as
Genetic
There are multiple genetic lesions associated with rhabdomyosarcoma, but there has been little consistent data demonstrating an association between specific genetic abnormalities and outcome. However, alveolar and embryonal types of RMS can be distinguished cytogenetically, and identification of specific genetic lesions can allow for accurate classification of the ARMS subtype when the histopathological findings are equivocal or unclear. This is valuable for clinical practice as the alveolar type presents a higher risk to the patient and will often require more aggressive treatment than the embryonal type. Thus, ARMS is also referred to as Fusion Positive rhabdomyosarcoma (FP-RMS). Up to 90% of alveolar RMS cases present with a translocations of t(2;13)(q35, q14) or, less commonly, t(1;13)(p36, q15).
The fusion protein presents a potential therapeutic target, and in recent years more research has been conducted to clarify the role of PAX3-FOXO1 in FP-RMS. PAX3-FOXO1 is now known to drive key oncogenes such as MYC and MYCN by creating long-distance genetic interactions by super enhancers.[28] In this context, PAX3-FOXO1 both (1) drives the expression of MYC, MYCN and even MYOD1 (a transcription factor highly expressed in all RMS subtypes) but also (2) co-binds with these master transcription factors at super enhancers to support cancer growth.[28] Furthermore, it was demonstrated that FP-RMS subtypes were especially sensitive to inhibitors (such as JQ1) of a super enhancer bound protein BRD4.[28]
Embryonal RMS usually presents with a
The loss-of-function of
Diagnosis
Rhabdomyosarcoma is often difficult to diagnose due to its similarities to other cancers and varying levels of differentiation. It is loosely classified as one of the small-blue-round-cell tumors due to its appearance on an H&E stain. Other cancers that share this classification include neuroblastoma, Ewing sarcoma, and lymphoma, and a diagnosis of RMS requires confident elimination of these morphologically similar diseases.[14] The defining diagnostic trait for RMS is confirmation of malignant skeletal muscle differentiation with myogenesis (presenting as a plump, pink cytoplasm) under light microscopy.[5] Cross striations may or may not be present. Accurate diagnosis is usually accomplished through immunohistochemical staining for muscle-specific proteins such as myogenin, muscle-specific actin, desmin, D-myosin, and myoD1.[25][34][35] Myogenin, in particular, has been shown to be highly specific to RMS,[36] although the diagnostic significance of each protein marker may vary depending on the type and location of the malignant cells. The alveolar type of RMS tends to have stronger muscle-specific protein staining. Electron microscopy may also aid in diagnosis, with the presence of actin and myosin or Z bands pointing to a positive diagnosis of RMS.[5][34] Classification into types and subtypes is accomplished through further analysis of cellular morphology (alveolar spacings, presence of cambium layer, aneuploidy, etc.) as well as genetic sequencing of tumor cells. Some genetic markers, such as the PAX3-FKHR fusion gene expression in alveolar RMS, can aid in diagnosis. Open biopsy is usually required to obtain sufficient tissue for accurate diagnosis. All findings must be considered in context, as no one trait is a definitive indicator for RMS.[citation needed]
Staging
Following diagnosis and histopathological analysis, various
The current staging system for rhabdomyosarcoma is unusual relative to most cancers. It utilizes a modified TNM (tumor-nodes-metastasis) system originally developed by the IRSG.[11][12][37] This system accounts for tumor size (> or <5 cm), lymph node involvement, tumor site, and presence of metastasis.[14][37] It grades on a scale of 1 to 4 based on these criteria. In addition, patients are sorted by clinical group (from the clinical groups from the IRSG studies) based on the success of their first surgical resection.[37] The current Children's Oncology Group protocols for the treatment of RMS categorize patients into one of four risk categories based on tumor grade and clinical group, and these risk categories have been shown to be highly predictive of outcome.[34][38]
Tumor site | Risk classification |
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Head and neck (orbit), biliary tract, genitourinary (excluding bladder and prostate) | Favorable |
Cranial parameningial, bladder, extremities, prostate, other | Unfavorable |
Treatment
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Treatment of rhabdomyosarcoma is a multidisciplinary practice involving the use of surgery, chemotherapy, radiation, and possibly immunotherapy. Surgery is generally the first step in a combined therapeutic approach. Resectability varies depending on tumor site, and RMS often presents in sites that don't allow for full surgical resection without significant morbidity and loss of function. Less than 20% of RMS tumors are fully resected with negative margins. Rhabdomyosarcomas are highly chemosensitive, with approximately 80% of cases responding to chemotherapy. In fact, multi-agent chemotherapy is indicated for all patients with rhabdomyosarcoma. Before the use of adjuvant and neoadjuvant therapy involving chemotherapeutic agents, treatment solely by surgical means had a survival rate of <20%. Modern survival rates with adjuvant therapy are approximately 60–70%.[8][39]
There are two main methods of chemotherapy treatment for RMS. There is the VAC regimen, consisting of vincristine, actinomycin D, and cyclophosphamide, and the IVA regimen, consisting of ifosfamide, vincristine, and actinomycin D. These drugs are administered in 9–15 cycles depending on the staging of the disease and other therapies used.[34] Other drug and therapy combinations may also show additional benefit. Addition of doxorubicin and cisplatin to the VAC regimen was shown to increase survival rates of patients with alveolar-type, early-stage RMS in IRS study III, and this same addition improved survival rates and doubled bladder salvage rates in patients with stage III RMS of the bladder.[16][34] In children and young adults with stage IV metastatic rhabdomyoscarcoma, a Cochrane review has found no evidence to support the use of high-dose chemotherapy as a standard therapy.[40]
Radiation therapy, which kill cancer cells with focused doses of radiation, is often indicated in the treatment of rhabdomyosarcoma, and the exclusion of this treatment from disease management has been shown to increase recurrence rates. Radiation therapy is used when resecting the entirety of the tumor would involve disfigurement or loss of important organs (eye, bladder, etc.). Generally, in any case where a lack of complete resection is suspected, radiation therapy is indicated.[14] Administration is usually following 6–12 weeks of chemotherapy if tumor cells are still present. The exception to this schedule is the presence of parameningeal tumors that have invaded the brain, spinal cord, or skull. In these cases radiation treatment is started immediately.[41][42] In some cases, special radiation treatment may be required. Brachytherapy, or the placement of small, radioactive "seeds" directly inside the tumor or cancer site, is often indicated in children with tumors of sensitive areas such as the testicles, bladder, or vagina. This reduces scattering and the degree of late toxicity following dosing.[43] Radiation therapy is more often indicated in higher stage classifications.
Immunotherapy is a more recent treatment modality that is still in development. This method involves recruiting and training the patient's immune system to target the cancer cells. This can be accomplished through administering small molecules designed to pull immune cells towards the tumors, taking immune cells pulled from the patient and training to attack tumors through presentation with tumor antigen, or other experimental methods. A specific example here would be presenting some of the patient's dendritic cells, which direct the immune system to foreign cells, with the PAX3-FKHR fusion protein in order to focus the patient's immune system to the malignant RMS cells[citation needed]. All cancers, including rhabdomyosarcoma, could potentially benefit from this new, immune-based approach[citation needed].
Prognostic
Prognosis in rhabdomyosarcoma patients has been shown to be dependent on age, tumor site, resectability of tumor, tumor size, regional lymph node involvement, presence of metastasis, site and extent of metastasis, and biological and histopathological characteristics of the tumor cells.[44] Survival after recurrence is poor, and new salvage therapy strategies are needed.[citation needed]
Epidemiology
Rhabdomyosarcoma is the most common soft-tissue sarcoma in children as well as the third most common solid tumor in children. Recent estimates place the incidence of the disease at approximately 4.5 case per 1 million children/adolescents with approximately 250 new cases in the United States each year.[45][44] With the vast majority of cases of RMS occurring in children or adolescents, two-thirds of reported cases occur in youths under the age of 10.[5] RMS also occurs slightly more often in males than in females, with a ratio of approximately 1.3–1.5:1. In addition, slightly lower prevalence of the disease has been reported in black and Asian children relative to white children.[46][47][48] In most cases, there are no clear predisposing risk factors for the development of RMS. It tends to occur sporadically with no obvious cause. However, RMS has been correlated with familial cancer syndromes and congenital abnormalities including neurofibromatosis type 1,[49] Beckwith-Wiedemann syndrome,[50][51] Li–Fraumeni syndrome,[52] cardio-facio-cutaneous syndrome,[53] and Costello syndrome.[54] It has also been associated with parental use of cocaine and marijuana.[55]
History
Rhabdomyosarcoma was first described by Weber, a German physician, in 1845,[56] but it was not until the paper by Arthur Stout in 1946 that RMS was formally classified.[57] The first thirty years of investigation were conducted by the Intergroup Rhabdomyosarcoma Study Group (IRSG), an independent National Cancer Institute (NCI)-funded cooperative that has become a part of the Children's Oncology Group.[citation needed]
Research
See also
References
- ^ "What Is Rhabdomyosarcoma?". www.cancer.org. Archived from the original on 2020-09-17. Retrieved 2021-02-11.
- ^ S2CID 225430576.
- ISBN 9780323353175.)
{{cite book}}
: CS1 maint: location missing publisher (link - from the original on 2020-02-13. Retrieved 2021-02-07.
- ^ PMID 10423470.
- S2CID 46247372.
- S2CID 40778156.
- ^ PMID 7636557.
- PMID 1574030.
- ^ S2CID 22962204.
- ^ S2CID 23179823.
- ^ S2CID 25785779.
- PMID 26097732.
- ^ a b c d e f g Meyer, WH (2003). "Rhabdomyosarcoma". Holland-Frei Cancer Medicine (6th ed.). Hamilton (ON): BC Decker. Archived from the original on 2022-10-16. Retrieved 2017-09-10.
- S2CID 26946298.
- ^ S2CID 25505511.
- PMID 2723995.
- PMID 16921036.
- S2CID 1792514.
- PMID 11408506.
- ^ "Risk Factors for Rhabdomyosarcoma". www.cancer.org. Archived from the original on 2022-08-06. Retrieved 2021-02-11.
- PMID 29762508.
- ^ from the original on 2016-08-10. Retrieved 2016-05-23.
- ^ S2CID 794511.
- ^ S2CID 23071344.
- ^ PMID 7530783.
- PMID 9164192.
- ^ PMID 28446439.
- S2CID 8160066.
- from the original on 2022-10-16. Retrieved 2019-09-16.
- PMID 8764111.
- S2CID 25993698.
- ^ S2CID 206694560.
- ^ PMID 10337369.
- S2CID 46691289.
- S2CID 21756898.
- ^ S2CID 37393818.
- PMID 3950676.
- S2CID 25749451.
- PMID 21154373.
- S2CID 22713795.
- PMID 11835233.
- PMID 7772200.
- ^ from the original on 2022-08-19. Retrieved 2017-09-10.
- PMID 19536876.
- ^ Wexler, LH; Herman, LJ (1997). Principles and practice of pediatric oncology. 3rd ed. Philadelphia: Lippincott-Raven. pp. 799–829.
- PMID 1654982.
- PMID 8153013.
- S2CID 23924644.
- S2CID 8824095.
- S2CID 36360747.
- PMID 1978757.
- PMID 10524458.
- PMID 11857556.
- from the original on 2022-07-03. Retrieved 2020-03-29.
- from the original on 2022-11-14. Retrieved 2022-11-14.
- PMID 17858752.
- PMID 24467821.
- Saboo, S. S.; Krajewski, K. M.; Zukotynski, K.; Howard, S.; Jagannathan, J. P.; Hornick, J. L.; Ramaiya, N. (2012). "Imaging Features of Primary and Secondary Adult Rhabdomyosarcoma". American Journal of Roentgenology. 199 (6): W694–W703. PMID 23169742.