Rhabdomyosarcoma (RMS) tumors are the most common soft-tissue sarcomas in childhood. In this investigation, we show that myostatin, a skeletal muscle-specific inhibitor of growth and differentiation is expressed and translated in the cultured RMS cell line, RD. The addition of exogenous recombinant myostatin inhibits the proliferation of RD cells cultured in growth media, consistent with the role of myostatin in normal myoblast proliferation inhibition. However, unlike normal myoblasts, upregulation of p21 was not observed. Rather, myostatin signalling resulted in the specific downregulation of both Cdk2 and its cognate partner, cyclin-E. The analysis of Rb reveals that there was no change in its phosphorylation status with myostatin treatment, consistent with D-type-cyclin–Cdk4/6 complexes being active in the absence of p21. Moreover, the activity of Rb appeared to be unchanged between treated and nontreated RD cells, as determined by the ability of Rb to bind E2F1. The examination of NPAT, a substrate of cyclin-E–Cdk2 involved in the transcriptional activation of replication-dependent histone gene expression, revealed that it undergoes a loss of phosphorylation with myostatin treatment. Supporting this, a downregulation in H4-histone gene expression was observed. These results suggest that myostatin could potentially be used as an inhibitor of RMS proliferation and define a previously uncharacterized, Rb-independent mechanism for the inhibition of muscle precursor cell proliferation by myostatin.

Keywords:

myostatin, NPAT, rhabdomyosarcoma, retinoblastoma; histone

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Germ-cell tumours are rare and generally occur in the testis and ovaries, as well as the mediastinum or retroperitoneum. Mediastinal germ-cell tumours in adult patients represent 2–5% of germ-cell tumours and only 1–10% of mediastinal tumours [1–3]. Germ-cell tumours are observed both in children below 7 years of age and in young adults from 15 to 35 years of age [4, 5]. They are more frequent in male patients. Primary mediastinal germ-cell tumours have the same histological pattern as their gonadal counterpart. One possible categorization of mediastinal germ-cell tumours is as follows.

Seminomas (less frequent than non-seminomatous tumours).

Non-seminomatous germ-cell tumours (NSCGT), which may have different pathological aspects—embryonal carcinoma or choriocarcinoma—which are frequently associated [2]. One of the most frequent and characteristic aspects is pure yolk sac tumour.

Mature teratoma.

Mixed NSCGT or mixed seminomas: the association of germ-cell tumours and non-germinal components, as has been described previously [6, 7].

Moreover, mediastinal germ-cell tumours are often associated with haematological malignancies that develop from yolk sac elements [8]. The prognosis of mediastinal germ-cell tumours is poor: only 30% of patients are cured [3].

We report on a case of mediastinal germ-cell tumour associated with embryonal rhabdomyosarcoma. Such an association is rare in adult patients.

CASE REPORT

Mr T.A. was a 44-year-old non-smoker who had no antecedent and, in particular, no prior cryptorchidy. He came to our department with intermittent chest pain, a cough and recent hoarseness. The clinical examination was not informative. Chest X-rays showed a mediastinum enlargement. Retrospective analysis of a chest X-ray performed 2 years earlier (because of chronic interscapular pain) showed the presence of a heterogeneous opacity of the superior and anterior compartment of the mediastinum, something that was missed at the time. The maximum transversal diameter was 5.4 cm and the mediastinum/thorax ratio was 25%. Flexible fibreoptic bronchoscopy did not show any abnormality. Serum -fetoprotein (AFP) and human chorionic gonadotropin (hCG) levels were 491 IU/ml and <3 IU/l, respectively (normal values, less than 10 and 5, respectively). The computed tomography (CT) scans of the brain and abdomen were normal. Bone marrow aspiration did not show any abnormality. Tumour biopsy was performed by mediastinoscopy. The histological pattern was an association of embryonal carcinoma, yolk sac tumour and embryonal rhabdomyosarcoma. An immunohistochemical study showed a strong staining of anti-AFP antibodies in the yolk sac component and a positive reaction to anti-vimentine, anti-actine and anti-desmine antibodies in the rhabdomyosarcoma component. Clinical and ultrasonography examination of the testicles were normal. The diagnosis of NSCGT with embryonal rhabdomyosarcoma component was accepted at presentation.

The patient received three cycles of the standard BEP regimen of chemotherapy (30 mg bleomycin 1 day every week, 100 mg/m2/day etoposide and 20 mg/m2/day cisplatin from day 1 to day 5 every 3 weeks). He experienced a partial response on the CT scan with normalization of the serum AFP level after the first cycle of chemotherapy. The tolerance of chemotherapy was fair. After three cycles of chemotherapy, the patient had a surgical resection of the residual tumour that was adherent to the mediastinal vessels (right and left brachioencephalic vessels) and to the trachea. The resection was incomplete. The histological pattern was a mature teratoma with nervous and chondroid elements and presence of viable embryonal rhabdomyosarcoma.

It was decided to switch to a salvage chemotherapy regimen that aimed to treat the sarcomatous part of the tumour. The patient received alternating cycles of chemotherapy: carboplatin, epirubicin, vincristine (CEV), ifosfamide, vincristine, actinomycin (IVA) and ifosfamide, vincristine, etoposide (IVE). This treatment was poorly tolerated. The patient received three cycles but the tumour progressed in the medi-astinum (occurrence of a vena cava syndrome) with pleural effusion and lung metastasis.

Radiotherapy to the mediastinum had a palliative effect on the local compression. The serum AFP level remained within normal limits. However, proof of progression of the embryonal rhabdomyosarcoma component was obtained by bone marrow aspiration, which was indicated by the occurrence of anaemia and thrombocytopenia. The patient died of disease progression and cranial haemorrhage 8 months after diagnosis.

DISCUSSION

Mediastinal germ-cell tumours exhibit poor prognosis. Only 30% to 40% of patients are cured [2]. Moreover, long-term survivors may experience the occurrence of haematological malignancies with an incidence of 10% to 20% [8]. A more infrequent event was the development of a non-germinal malignant tumour within a germ-cell tumour [5]. This observation was first recognised in teratomatous elements after chemotherapy in testis cancer [6, 7]. This malignant transformation of teratomas was also described in mediastinal germ-cell tumours [9]. These malignant transformations are generally sarcomas and mostly rhabdomyosarcomas [10]. However, adenocarcinomas, neuroblastomas and other types of tumours have been observed [11]. The occurrence of both germ and non-germ-cell elements at diagnosis, before chemotherapy, has been described only in a few series or case reports [10, 11]. Our observation is a case of such an initial combination of two kinds of tumours.

Using cytogenetic arguments, the relationship between the germ-cell tumour and the embryonal rhabdomyosarcoma has been established. Germ-cell tumours have a common specific cytogenetic marker: the presence of the isochromosome [i(12p)] [12, 13]. This marker is also observed within the embryonal rhabdomyosarcoma component [14]. Moreover, the same chromosomal marker has been described in leukaemia associated with germ-cell tumours [14, 15]. It is derived from teratomatous elements of the germ-cell tumours. It also has been shown that haematopoetic stem cells may derive from yolk sac elements in mediastinal germ-cell tumours [16]. As malignant transformation of teratoma may occur both before and after chemotherapy, it seems very unlikely that chemotherapy might induce such a transformation. Conversely, it is probable that non-germ-cell elements derive from germinal stem cells. The mechanism of action of this transformation is unknown.

Occurrence of the sarcomatous component in a mediastinal teratoma has no specific initial clinical feature. Teratomas that are likely to progress to such an outcome can not be differentiated from others on the basis of clinical or radiological criteria [6]. Diagnosis can be fortuitous at the time of histopathological examination of a tumour biopsy or after tumour resection or, more frequently, as a result of an unusual outcome with chemotherapy of a presumed non-teratomatous germ-cell tumour [3, 5].

Sarcomatous components of germ-cell tumours, especially rhabdomyosarcoma, have a proper metastatic potential and a poor prognosis, particularly in adults and if the primary site is mediastinal [11]. This prognosis can be influenced by many factors such as resectability of the tumour and histopatho- logical subtype of the malignant component, its occurrence in a metastatic site and its sensitivity to chemotherapy [1, 6].

Embryonal rhabdomyosarcomas in adult patients are rare, mostly in the paratesticular area [10]. The prognosis is generally worse than that of their paediatric counterpart. Mediastinal rhabdomyosarcomas are most often resistant to chemotherapy. They have a poor prognosis, worse than their gonadal counterpart [10, 17], with a short survival of <2 years. Patients die mostly by regional involvement and multiple metastasis [5, 10]. At present, there is no standard schedule of chemotherapy in adult embryonal rhabdomyosarcoma and the paediatric protocols are often not effective in adults, and no chemotherapy is effective on both the germinal and non-germinal components. The most important prognostic factors in adult rhabdomyosarcomas are age, tumour size, extent of disease and complete resection [17]. The median survival in a population of 84 adult patients was 22 months, despite aggressive multimodality management (associated chemotherapy and surgery).

It is noteworthy that in our case, as in others, the germ-cell component of the tumour was very chemosensitive. However, the embryonal rhabdomyosarcoma was refractory to a chemotherapy regimen which is generally considered as effective in this tumour type. A review of the literature [1, 5, 6, 10, 19–22] shown in Table 1 demonstrates that the prognosis of this disease is poor (only one out of 16 patients is cured). Of the 15 patients with mediastinal germ-cell tumours, reported by Gonzalez-Vela [19], four with sarcoma components died of disease, but six of 11 without sarcoma components lived. Experience proves that surgery is a very important part of treatment, and as is the case in active germ-cell residual tumours, complete surgical resection appears to be the most important prognostic factor of survival [23]. At present, little information concerning the disease’s behaviour and treatment modalities is available.

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Richard J. Davis¹, Jeannette L. Bennicelli¹, Roberto A. Macina³, Lynn M. Nycum⁴, Jaclyn A. Biegel^2,4 and Frederic G. Barr^1,*

¹Departments of Pathology and Laboratory Medicine 37th Street and Hamilton Walk, Philadelphia, PA 19104-6082 ²Departments of Pediatrics, University of Pennsylvania School of Medicine 37th Street and Hamilton Walk, Philadelphia, PA 19104-6082 ³The Wistar Institute 3601 Spruce Street, Philadelphia, PA 19104 ⁴Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia Philadelphia, PA 19104, USA

^*To whom correspondence should be addressed

Received August 23, 1995; Revised September 25, 1995; Accepted September 25, 1995

The FKHR gene, which contains a forkhead DNA-binding motif, is fused to either PAX3 or PAX7 by the t(2;13) or t(1;13) translocation in alveolar rhabdo-myosarcoma, respectively. These tumors express chimeric transcripts encoding the N-terminal portion of either PAX protein fused to the C-terminal portion of FKHR. To understand the structural basis and functional consequences of these translocations, we characterized the wild-type FKHR gene and its rearrangement in alveolar rhabdomyosarcomas. By isolating and analyzing phage, cosmid and YAC clones, we determined that FKHR consists of three exons spanning 140 kb and that several highly similar loci are present in other genomic regions. Exon 1 encodes the N-terminus of the forkhead domain and is embedded within a demethylated CpG island. RNA analyses reveal FKHR transcripts initiate from a TATA-less promoter within this island. Exon 2 encodes the C-terminus of the forkhead domain and a transcriptional activation domain, whereas exon 3 encodes a large 3′ untranslated region. The intron 1—exon 2 boundary precisely matches the FKHR fusion point in the chimeric transcripts found in alveolar rhabdo-myosarcomas. Using pulsed-field and fluorescence in situ hybridization analyses, we demonstrate that the 130 kb FKHR intron 1 is rearranged in t(2;13)-containing alveolar rhabdomyosarcomas. Our findings indicate that FKHR intron 1 provides a large target for DNA rearrangement. Rearrangement of this intron with PAX3 produces two important functional consequences: in-frame fusion of N-terminal PAX3 sequences to the FKHR transcriptional activation domain and disruption of the FKHR DNA binding domain.

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Rhabdomyosarcoma is primarily a childhood tumor and occurs most often in children under 5 years of age. Over 60% of cases show up before age 10. On rare occasions, rhabdomyosarcoma affects adults.

Rhabdomyosarcoma can begin anywhere there is muscle including (in order of frequency) the head and neck, arms and legs, genitourinary tract, and the trunk.

Treatment for rhabdomyosarcoma may involve surgery, radiotherapy or chemotherapy. Usually two or three of these modalities of treatment are employed. For example, a surgeon may first try to remove as much tumor as possible. Then the patient may undergo several weeks of chemotherapy, possibly followed by radiation therapy, and then more chemotherapy.

The prognosis (outcome) with rhabdomyosarcoma depends on the location of the cancer, how far it has spread, the type of rhabdomyosarcoma, how much can be surgically removed, and the type of treatment received.

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This page contains recent news articles, when available, and an overview of Rhabdomyosarcoma but does not offer medical advice. You should contact your physician with regard to any health issues or concerns.

Background information on Rhabdomyosarcoma

A rhabdmyosarcoma is a form of cancer of the sarcoma subtype that shows differentiation or determination towards resembling skeletal muscle.

In general, as a result of oncogenesis, the cells comprising a cancer will have a different genotype to the constitutional genotype of the host. The genotypic changes may induce a perceptible change in the phenotype. Both of these changes may be used to classify the neoplasm. Medically useful systems of classification offer the means for diagnosis and prognosis, and may assist the physician in the choice of optimal treatment.

The cells in a particular cancer might show no overt differentiation or they might show varying degrees of differentiation that parody the appearances of some normal tissue. In a histogenetic classification, the cancer is named for the normal tissue whose phenotype is most closely mimicked. A cancer whose cells show no resemblance to any particular tissue is said to be undifferentiated. The differentiation may be perceived at the level of tissue architecture (that is, how the individual cells group together and organise themselves compared with normal tissues). An assessment of architectural relationships is the most important part of histopathology. It provides an important means to predict the biological behaviour of a neoplasm, that is, to form an opinion whether it will behave in a benign or malignant fashion. Assessment of individual cells is the main subject of cytopathology. Cytopathological assessment of cellular phenotype is best undertaken on suitably prepared whole cells that have been spread onto a glass slide. However, with some limitations, it may also be undertaken on those individual cells that form part of a neoplasm that are present in a thin section of a biopsied specimen.

Light microscopy may be used to assess the architecture of sampled tissues and the phenotype of its cells. A biopsied specimen is typically hardened and preserved in some suitable fixative. It is dehydrated and embedded in paraffin wax to allow thin sections to be taken onto glass slides. Routine assessment of these sections involves rehydration and staining with haematoxylin (which stains acidic molecules, such as nucleic acids, blue) and eosin (which stains basic molecules, such as proteins, red).

The cellular phenotype may also be assessed at the higher magnifications afforded by electron microscopy. The biopsied specimen is processed in a similar way, except that the fixatives, embedding media and stains are chosen to allow the generation of thinner sections and differential opacity to transmitted electrons rather than photons.

A change in the phenotype of a cell is effected by changes in the proteins within its cytoplasm. When this is visible using light microscopy, it may be possible to use this cellular phenotype to classify the cancer. In a rhabdomyosarcoma, the accumulation in a variable proportion of the malignant cells of large amounts of the particular isomers of the proteins that are responsible for the contractile properties of skeletal muscle typically result in large cells with cytoplasm that stains deeply red with eosin. In a small number of the malignant cells these proteins might be assembled in a structured way that imparts the “striated” appearance, characterised by alternating bands of dark and pale red, that is typical of normal skeletal muscle.

In poorly differentiated cells, the proteins that accumulate may not be present in sufficient quantities to produce a perceptible change in the appearance of the cell as judged by light microscopy. It is possible to probe for the presence of these proteins using other techniques such as immunohistochemistry. In the absence of a perceptible change in the cellular phenotype, this provides an opportunity to identify an “immunophenotype”. Using this technique, the presence of proteins such as desmin, myoglobin, muscle specific actin, and others would provide strong evidence for the diagnosis of rhabdomyosarcoma.

Some cancers do not contain cells that are sufficiently differentiated to allow histogenetic classification by assessment of the cellular phenotype or immunophenotype. In some of these cells, it may be possible to identify other proteins whose presence indicates “determination” toward some particular tissue type. A cell that is “determined” has undergone modification of its genome so that the pathways of differentiation that remain open to it are restricted to those that are associated with the cells of some specific tissue. During the early stages of development of skeletal muscle cells, a protein called “myo D1″ binds itself to genetic material in the cell nuclei. This is an indicator of determination towards skeletal muscle differentiation. Once skeletal muscle cells become innervated by nerve cells, the concentration of this protein falls dramatically. The same protein (myo D1) may be found in the nuclei of the cells in a rhabdomyosarcoma. As the malignant cells do not become innervated by nerve cells, this protein remains in a high concentration. This may be exploited as a means to identify malignant neoplasms that contain cells that show determination towards rhabdomyosarcoma, even when there is insufficient differentiation to allow phenotypic assessment to be used for the diagnosis. As this protein may also be present in the cytoplasm of cells of other neoplasms whose other characteristics show that they are not rhabdomyosarcomas, demonstration of the presence of myo D1 should be considered supportive for rhabdomyosarcoma only if the protein is present in the cell nuclei.

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Rhabdomyosarcoma (RMS) is a very rare malignant tumor (“cancer”) that arises from a normal skeletal muscle cell. Dr. Leonard Wexler of Memorial Sloan Kettering Cancer Center has written an in-depth article, Rhabdomyosarcoma (RMS) for our Electronic Sarcoma Update Newsletter (ESUN). His article gives an extensive set of references to articles dealing with this disease. We are grateful to Dr. Wexler, an extremely busy pediatric oncologist and researcher, for finding the time to undertake this project. Click on the above link to view his article.  

There are over 50 subtypes of sarcoma. The American Cancer Society’s Key Statistics About Sarcoma states that the most common types of soft tissue sarcoma are: MFH or Malignant Fibrous Histiocytoma (28%), liposarcoma (15%), LMS or leiomyosarcoma (12%), synovial sarcoma (10%), malignant peripheral nerve sheath tumors (6%), and rhabdomyosarcoma (5%). All of the other types of soft tissue sarcoma occur at percentages of 3% or less. The ACS’ Key Statistics for Bone Cancer states that the most common types of bone cancer are osteosarcoma (35%), chondrosarcoma (26%), Ewing’s bone sarcoma (16%), chordoma (8%), and malignant fibrous histiocytoma/fibrosarcoma (6%). Other rare bone cancers account for the remaining 9%.

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Rhabdomyosarcoma is a type of soft tissue cancer that is most often found in children. This cancer will usually present itself as a noticeable lump. Since this is a cancer made up of cells that normally develop into skeletal muscles, the lump can appear in different locations of the body. Although most of our skeletal muscles are in our limbs and truck, it is usually found elsewhere.

The most common sites that rhabdomyosarcoma tumors are found:

—      Head and Neck (30%-40%)

—      Urinary and Reproductive Organs (20%-25%)

—      Arms and Legs (18%-20%)

—      Truck (7%)

There are two main types of rhabdomyosarcomas that occur in children, embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma. The embryonal type (ERMS) is the most common type and usually occurs in infants and young children. The alveolar type (ARMS) usually effects older children and teenagers. Embryonal has a better prognosis than alveolar, which is a more aggressive tumor type.

About 3 percent of childhood cancers are diagnosed as rhabdomyosarcoma. In the United States about 350 new cases arise each year. It is the most common type of sarcoma occurring in the soft tissues, which is tissue that lies between the skin and the bone. It is the sixth most common cancer in children.

The researchers say there are no known environmental risk factors that cause rhabdomyosarcoma. There are some inherited conditions that can increase the risk of developing rhabdomyosarcoma but these are only a small fraction of those diagnosed. L-Fraumeni syndrome, Beckwith-Wiedemann syndrome, neurofibromatosis and Costello syndrome are inherited conditions that are known to lead to different forms of cancer. This information gives the researchers of this disease some key knowledge in understanding the disease and points them in the direction of a genetic cause for this type of cancer.

There are four stages of rhabdomyosarcoma that is discussed. Survival rates depend on the type of rhabdomyosarcoma, whether it is ERMS or ARMS, the stage of the disease and also the clinical grouping that is also done along with staging.

The clinical groupings consist of:

—      Group I: localized disease with no spread elsewhere in the body, the tumor is completely removed by the surgeon and no lymph nodes are involved. Five year survival rate is over 90 percent.

—      Group II: cancer has been found at the edge of the removed tumor which suggests disease left behind, lymph nodes are involved. Five year survival rate is around 70 percent.

—      Group III: tumors cannot be completely removed and can be seen with the naked eye, no evidence of distant spread. Five year survival is around 55 percent.

—      Group IV: evidence of distant spread at time of diagnosis. Five year survival rate is around 20 to 25 percent.

Age of the patient, site of tumor and the type of tumor will effect these numbers. It is important to examine the clinical grouping and stage of the patient to determine the best treatment option. Treatment for rhabdomyosarcoma is usually a combination of surgery, chemotherapy and radiation.

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Rhabdomyosarcoma is usually seen in the first decade of life. Though the presentation of rhabdomyosarcoma in adults is very rare, it has been reported. ^[5],[6] In one study by Boparai and Dash, the oldest patient was 19 years whereas in the Chinese-American collaborative study, 4 out of 61 cases were above 20 years of age, the oldest being 56 years of age. ^[5] Pleomorphic rhabdomyosarcoma was suggested to occur more commonly in the older age groups. ^[6] The oldest in our series was of 29 years of age and had the embryonal type.

The finding of proptosis in children as the most common presenting sign in our patients underlines the importance of orbital rhabdomyosarcoma in the differential diagnosis of such a presentation. Jones et al. , have reported that 100% of the cases in their study had proptosis. ^[7] However, Schinter et al. , have documented 71% of cases with proptosis. ^[8] Boparai and Dash, in their case series had eleven out of 14 cases presenting with acute onset proptosis with inflammatory signs. ^[2] Four out of the six patients in our study presented with acute onset proptosis associated with signs of inflammation such as chemosis, congestion, tenderness and one patient was febrile. Hence rhabdomyosarcoma mimicking as orbital cellulitis is an important consideration to be kept in mind.

It was initially believed that the most common location of the tumor was the superonasal orbit, however, this has not been substantiated by others. ^[7] This has in fact been exemplified by the varying locations of the tumor seen in our series. Hence, in general, masses arising in other areas of the orbit in children must not be disregarded. There are also case reports on rhabdomyosarcoma in which the cases have presented as palpable lid nodules and on occasion felt to be a chalazion, cystic lesions or lid tumor of vascular origin. ^{[8],[9],[10],[11]} Such an atypical presentation was also seen in our study (upper lid mass with mechanical ptosis). Awareness about these less common presentations of this fatal malignancy is essential to ensure early detection and initiation of treatment.

X-ray is not of much help in the diagnosis but CT scan gives an idea of the total extent of the lesion. CT scan is also of tremendous value in follow up to detect recurrence.

None were found to have metastatic disease at onset, but in the adult patient, the tumor spread to ethmoid and maxillary sinuses over time even after receiving chemotherapy and radiotherapy. This shows the aggressive nature of these tumors especially when it occurs in the older age group. Recurrence or metastatic spread following rhabdomyosarcoma usually occurs within the first three years after treatment. One of our patients developed recurrent disease at the ninth month. Sutow and co-workers found that six of the 14 cases in their study had recurrence or metastatic spread within the first year after diagnosis. ^[12] However, recurrence following treatment of rhabdomyosarcoma as late as six years has also been reported. ^[3] Hence the need for long term follow-up of these patients treated for orbital rhabdomyosarcoma.

Four histopathological subtypes of rhabdomyosarcoma have been described: embryonal, alveolar, botryoides and pleomorphic. ^[3] It is believed that the embryonal, alveolar and botryoides variants are of mesenchymal origin and that the pleomorphic variant is derived from mature skeletal muscle. The pleomorphic type is the most differentiated type and carries the best prognosis followed by the embryonal and botryoides types. ^[3],[5] The alveolar type has been shown to carry the worst prognosis. ^[3],[5] Of the three cases that needed exenteration in our study, one case was alveolar rhabdomyosarcoma and two were of embryonal type. Embryonal rhabdomyosarcoma occurs most frequently, accounting for about 71% and 67% cases of orbital rhabdomyosarcoma. ^[2],[9] Our study also showed similar frequency with five (83%) cases proving to be embryonal rhabdomyosarcoma.

The practical difficulties need to be considered while obtaining biopsy or doing fine needle aspiration cytology in these patients. The biopsy, in rhabdomyosarcoma is a difficult procedure because the vascularised tumor may result in severe bleeding, hindering the surgical procedure and this may be compounded by the severe chemosis or lid edema associated with this condition.

Earlier orbital rhabdomyosarcoma was treated by orbital exenteration. In 1979, Abraham et al. demonstrated irradiation alone or in combination with chemotherapy to be more effective than exenteration for both control and long-term survival. ^[11] Reports of the efficacy of combined radiotherapy and chemotherapy were confirmed by the Intergroup Rhabdomyosarcoma Study, which showed a three-year survival rate of 93% in a total of 127 patients with localized orbital rhabdomyosarcoma. ^[13] Radiotherapy and chemotherapy have also been enlisted in treatment of local recurrences and metastatic disease. ^[14] In our series of patients, we have noted complete regression of the tumor with chemotherapy and radiotherapy in two cases and with only chemotherapy in one case. However, in the remaining three patients, exenteration had to be performed despite prior treatment with chemotherapy and radiotherapy, as the regression was not complete. The exenteration procedure for such cases of refractory rhabdomyosarcoma was found to be of value in prolonging the survival rate. ^[15]

In conclusion, the primary modality of treatment of rhabdomyosarcoma is combined radiotherapy and chemotherapy, which appears to permit effective control and possible cure of this disease. At the time of biopsy, maximum debulking is essential. Exenteration is mutilating and induces the most unfortunate cosmetic appearance postoperatively. However, exenteration may be indicated in cases of incomplete tumor regression or in cases of recurrence after treatment with chemotherapy and radiotherapy. Judgment by the experienced therapist may be valuable in maximizing the gain and minimizing the risk of therapy in individual cases.

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Staging is the process of finding out how far a cancer has spread. The outlook for chances of survival (prognosis) for people with cancer depends, to a large extent, on the cancer’s stage. The stage of a cancer is one of the most important factors in choosing treatment.

Your child’s doctors will use the results of the imaging tests (described in “How Is Rhabdomyosarcoma Diagnosed?”), the pathologist’s biopsy reports, and the direct examination of the organs during surgery to determine how far the cancer has spread. If there is any doubt about the presence or absence of cancer, more biopsies may be done on tissue at the edge of the tumor, nearby lymph nodes, and any suspicious lumps in other parts of the body.

Staging for rhabdomyosarcoma is fairly complex. Doctors first determine 3 key pieces of information:

—      the type of rhabdomyosarcoma (embryonal vs. alveolar) 

—      the clinical group 

—      the TNM stage

These factors are then used to divide patients into risk groups, which in turn are used to determine the best treatment options.

Clinical groups

The clinical group is based on the extent of the disease and how completely it is removed during initial surgery. Briefly, the groups are defined as follows.

Group I

This group includes children with localized disease (the cancer has not spread to nearby lymph nodes or to distant sites in the body) and there is no evidence of any tumor left behind after surgery. Group I has 2 subgroups:

Group IA: Children in this group had a tumor that was still confined to the muscle or organ where it started and it was completely removed by surgery. It had not spread to nearby lymph nodes or distant sites.

Group IB: Children in this group had a tumor that had grown beyond the muscle or organ where it started and into nearby structures, but it was completely removed by surgery. It had not spread to nearby lymph nodes or distant sites.

About 15% of rhabdomyosarcoma patients are in group I.

Group II

This group includes children who have had tumors that have been removed by surgery, but cancer has been found either around the edges of the removed specimen or in the lymph nodes. In both cases, as much of the cancer has been removed as possible. Group II has 3 subgroups:

Group IIA: In this group, the surgeon has removed all the cancer that could be seen, but the pathologist has found cancer at the edge of the removed specimen, which means that there is a small amount of cancer left behind. It has not spread to nearby lymph nodes or elsewhere.

Group IIB: In this group, the cancer has spread to nearby lymph nodes, but all of the cancer has been removed by surgery.

Group IIC: In this group, the cancer has spread to nearby lymph nodes. The surgeon has removed all the cancer that could be seen (including in the lymph nodes), but the pathologist has found cancer at the edge of the removed specimen, which means that there is a small amount of cancer left behind.

About 20% of patients are in group II.

Group III

These children have tumors that cannot be completely removed, leaving some tumor behind that can be seen with the naked eye. The tumor may have spread to nearby lymph nodes, but there is no sign that it has spread to distant organs.

Group III has 2 subgroups:

Group IIIA: The tumor cannot be completely removed by surgery, and only a biopsy of the tumor has been done.

Group IIIB: The tumor cannot be completely removed, but surgery has removed at least half of the tumor.

This group accounts for about 50% of patients with rhabdomyosarcoma.

Group IV

These children have evidence of distant spread at the time of diagnosis to places such as the lungs, liver, bones, bone marrow, or to distant muscles or lymph nodes.

This group contains about 15% of children with rhabdomyosarcoma.

The TNM stage

The TNM stage doesn’t depend on the results of surgery, but on the type and size of the tumor, its invasion of the lymph nodes and distant organs, and where it starts. It is based on 3 key pieces of information:

—      T: the characteristics of the tumor 

—      N: whether the cancer has spread to nearby lymph nodes 

—      M: whether it has metastasized (spread) to distant parts of the body

These factors are combined to determine an overall stage:

Stage 1: The tumor started in a favorable area:

—      the orbit (area near the eye) 

—      the head and neck area, except for parameningeal sites (next to the membranes covering the brain) 

—      a genital or urinary site, except the bladder or prostate 

—      biliary tract (tubes leading from the liver to the intestines)

The tumor can be any size. It may have grown into nearby areas and/or spread to nearby lymph nodes, but it has not spread to distant sites.

Stage 2: The tumor started in an unfavorable site:

—      the bladder or prostate 

—      an arm or leg 

—      a parameningeal site (next to the membranes covering the brain) 

—      any other site not mentioned in stage 1

The tumor is smaller than 5 cm (about 2 inches) across and there is no evidence that it has spread to nearby lymph nodes or distant sites.

Stage 3: The tumor started in an unfavorable site:

—      the bladder or prostate 

—      an arm or leg 

—      a parameningeal site (next to the membranes covering the brain) 

—      any other site not mentioned in stage 1

One of the following applies:

—      the tumor is smaller than 5 cm across but has spread to nearby lymph nodes 

—      the tumor is larger than 5 cm across and may or may not have spread to nearby lymph nodes

In either case, the cancer has not spread to distant sites.

Stage 4: The tumor can have started at any site and can be of any size. It has spread to distant sites such as the lungs, liver, bones, or bone marrow.

Risk groups

With the information about the type of rhabdomyosarcoma, the clinical group, and the TNM stage, doctors then classify patients into 3 risk categories . These risk groups help doctors decide how aggressive treatment should be.

Clinical risk groups are defined based on what we have learned from previous research and the outcomes of patients. The risk groups discussed below are based on the most current information, but these may change in the future as safer and more effective treatments are developed.

Low-risk group

This group includes:

—      children with TNM stage 1 embryonal rhabdomyosarcomas (ERMS) that fall into clinical groups I, II, or III

—      children with stage 2 or 3 ERMS who are in clinical groups I or II

Intermediate-risk group

This group includes:

—      children with stage 2 or 3 ERMS who are in clinical group III

—      children with stage 4 ERMS (any group) who are younger than 10 years old

—      children with alveolar rhabdomyosarcoma (ARMS) that has not spread to distant sites (stage 1, 2, or 3)

High-risk group

This group includes:

—      children with widespread (stage 4) ARMS

—      children with widespread (stage 4) ERMS who are 10 years old or older

Five-Year survival rates by risk group

Below are general survival statistics based on risk groups. These numbers come from large clinical trials treating children with rhabdomyosarcoma in the 1980s and 1990s. Survival statistics can be complex, and there are some important points to note about these numbers:

—      The 5-year survival rate refers to the percentage of patients who live at least 5 years after being diagnosed. They are used to produce a standard way of discussing prognosis (the outlook for recovery and survival). Of course, many people live much longer than 5 years.

—      These numbers are among the most current we have available, but they represent children who were first diagnosed and treated many years ago. Improvements in treatment since then mean that the survival rates for those now being diagnosed with these cancers may be higher.

—      Although survival statistics can sometimes be useful as a general guide, they may not accurately represent any one child’s prognosis. A number of other factors, including tumor characteristics (such as where it started, the tumor type, and where and how far it has spread) and a child’s age, also affect outlook. Your child’s doctor is likely to be a good source as to whether these numbers may apply to your child, as he or she is familiar with the aspects of the particular situation.

Low-risk group: Overall, the 5-year survival rate for children in the low risk group is over 90%. Most of these children will be cured.

Intermediate-risk group: For those in the intermediate risk group, the 5-year survival rates range from about 50% to about 70%. The rate varies somewhat by tumor location, stage, and the age of the child.

High-risk group: If the cancer has spread widely, the 5-year survival rate is generally around 20% to 25%. Again, it’s important to note that other factors, such as the age of the patient and the site and type of tumor will all affect these numbers. For example, children with embryonal rhabdomyosarcoma and limited spread (to only 1 or 2 distant sites) have a higher 5-year survival rate.

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CASE 1. Hypermethylation in Orbital Alveolar Rhabdomyosarcoma

Wai-Man Chan, David T.L. Liu, Chi-Pui Pang, Dennis S.C. Lam

Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, People’s Republic of China

Ka Fai To, Paul C.L. Choi

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

Kwong Wai Choy

Department of Ophthalmology and Visual Sciences; Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

Chun-Yu Wong, Dylan D.N. Chan

Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, People’s Republic of China

A 10-month-old boy, born full term in Hong Kong, presented with increasing right-eye proptosis for 2 months. The parents had noted a concomitant right lower eyelid coin-sized swelling with violaceous skin discoloration. It was managed as a lower eyelid chalazion by several ophthalmologists initially with oral antibiotic treatment and then incision and curettage. The procedure, however, drained no pus, and computed tomography (CT) of orbit showed a huge contrast-enhancing soft tissue mass infiltrating the right inferior rectus muscle. On referral, a 2 x 2 cm solitary right lower lid, firm to hard, nontender mass could be palpated. There was no fluctuance and it was not possible to get behind the mass. No tethering to surrounding tarsus could be demonstrated. The right proptosis was nonaxial with upward displacement of the globe. Both the depression and elevation of the right globe were restricted. The intraocular pressure and fundal examination of both eyes were normal. No cervical lymphadenopathy could be palpated. Systemic review was unremarkable and no important neonatal or family history was noted. Magnetic resonance imaging of orbit confirmed the presence of a 3 x 2.7 x 3-cm tumor mass, which arose predominantly from inferior rectus muscle, extending into the right retrobulbar region (Fig 1). The signal density was heterogeneous, suggestive of internal necrosis. The optic nerve had been displaced by tumor but neither invasion nor compression were seen. The optic foramen was not widened. Both the medial wall and floor of orbit appeared to be invaded, whereas the lateral wall and orbital roof stayed clear. The tumor was abutting the medial rectus, but there was no sign of invasion. Other extraocular muscles and pterygopalatine fossa were spared. No intracranial extension could be seen. A transconjunctival incisional biopsy under general anesthesia was arranged in liaison with neonatologist and anaesthesiologist. Histopathologic examination revealed clusters and sheets of tumor cells of polygonal to spindle shape with nuclear pleomorphism, stippled chromatin, distinct nucleoli, and eosinophilic cytoplasm among the fibrous stroma diagnostic of rhabdomyosarcoma (Fig 2). The tumor cells exhibited strong and diffuse positive staining for desmin and myogenin by immunohistology analysis, whereas other immunomarkers were negative (Fig 3). We also carried out molecular hypermethylation profiling of 27 genes that frequently show hypermethylation in human cancers (Fig 4). Methylation-specific polymerase chain reaction (PCR) analyses of DNA from alveolar rhabdomyosarcoma tumor demonstrated that existence of PCR products in lane M indicates the presence of methylated alleles, and in lane U unmethylated alleles. Four of twenty-seven genes were methylation positive (RB1, HIC1, HIN-1, and CDX-1), and the rest were methylation negative. Representative example of negative control (water) and positive control (CTL) for COX2 was shown. The analysis included well-characterized tumor suppressor genes, DNA repair genes, and genes related to metastasis and invasion.^{1, 2} Among them, promoter hypermethylation was identified in only four tumor suppressor genes: HIC1, HIN-1, RB1, and CDX-1. It is notable that there was no detectable promoter hypermethylation for the myogenic marker MyoD1. A whole-body CT staging consisting of CT of brain, neck, thorax and abdomen was performed and showed absence of metastases. Bone marrow examination and bone scan were negative for neoplastic infiltration. CBCs, biochemical profiles, clotting, and serum immunoglobulins were all normal. The right orbital alveolar rhabdomyosarcoma was categorized as group 3, stage I, T1a, N0 and M0 disease. Chemotherapy in accordance with the International Rhabdomyosarcoma Study (IRS) with the VAC regimen (vincristine, 0.025 mg/kg; dactinomycin, 0.025 mg/kg; and cyclophosphamide, 36 mg/kg) for 40 weeks was initiated. In addition, right transconjunctival debulking surgery of the inferior rectus tumor was performed, followed by local external beam radiotherapy. Both the systemic and ocular conditions of the patient were stabilized.

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