Rhabdomyosarcoma: a rare laryngeal neoplastic entity

Summary

A case of pleomorphic rhabdomyosarcoma of the larynx is presented, which is extremely rare in a laryngeal site. The symptomatology and macroscopic aspect of the neoplasm can simulate the presence of other neoplastic variants of the larynx, and, for this reason, histological examination must be associated with immunohistochemistry for correct diagnosis and treatment.

Introduction

Rhabdomyosarcoma (RMS) is the most frequent soft tissue tumour in paediatric patients, accounting for up to 50% of all soft tissue sarcomas ¹, while in adults, RMS may represent about 15-20% of all soft tissue sarcomas ². The neoplasm has a mesenchymal origin and involves skeletal muscle, and can, therefore, be localized in almost any site. In paediatric patients, it is most frequently localized to the cervical-cephalic and genito-urinary regions; in adults, RMSs involving the thorax and extremities account for 2-5% of all soft tissue sarcomas ³. Three histological subtypes have been identified: embryonal with the botryoid and alveolar histiotypes that generally affect young children and adolescents ⁴, and the pleomorphic histiotype that is usually encountered in adult patients ². RMS is a malignant neoplasm characterized by extensive loco-regional spread and a tendency for secondary seeding through lymphatic and haematological routes.

Since 1972, the Intergroup Rhabdomyosarcoma Study Group (IRSG) has conducted a series of prospective randomized trials aimed at improving cure rates, while minimizing treatment-related morbidity, using combined modality treatment (surgery, radiotherapy and chemotherapy). Four successive protocols (IRS-I; IRS-II; IRS-III; and IRS-IV) were illustrated ^5–8. Currently, IRSG is enrolling patients in IRS-V ⁸.

Case report

A 75-year-old male was referred to our attention in April 2006 with dysphonia that had been worsening for approximately one year. Objective examination revealed a bilateral leukoplakia localized in the true vocal cords. The patient was submitted to microlaryngoscopy, and a biopsy was taken, the histological examination of which showed hyperkeratosis of the vocal cords with slight basal dysplasia. The patient then underwent a full excisional biopsy. Follow-up was carried out monthly with laryngoscopic examination. In November 2007, the patient presented with a neoplasm on the left vocal cord with irregular margins and consequent reduction of the airway diameter; there was no clinically appreciable cervical lymphadenopathy. During the same month, direct microlaryngoscopy was performed, and a biopsy was taken from the neoplasm on the left vocal cord. Histological examination (Fig. 1A-D) showed the presence of fused cells of variable dimension, with eosinophilic cytoplasm, that were frequently irregular and hyperchromic with large or multiple nuclei. Immunohistochemical testing revealed staining of vimentin, actin and myogenin, which confirmed the diagnosis of pleomorphic RMS.

Fig. 1.

Pleomorphic rhabdomyosarcoma of larynx. Histology shows an exophytic, extensively ulcerated nodular lesion, characterized by proliferation of atypical spindle cells (A. H&E, magn. 200X) admixed with large, multinucleated round cells with abundant eosinophilic cytoplasm (B. H&E, magn. 400X); immunohistochemistry displays strong and diffuse positive cytoplasmic stain for smooth muscle actin (C. magn. 400X) and focally positive nuclear stain for myogenin (D. magn. 400X) in neoplastic cells.

Considering the histological diagnosis and the highly aggressive nature of the lesion, positron electron tomography (PET) and computerized tomography (CT) of the neck and thorax were performed, although no additional anatomical sites were affected by the neoplasm. In March 2008, the patient underwent partial left laryngectomy, with an uneventful post-operative recovery. Histological examination of the whole specimen confirmed the diagnosis of pleomorphic RMS; the surgical margins were negative for tumour involvement. The consulting oncologist did not recommend chemotherapy or radiotherapy given the complete surgical removal of the lesion.

So far, the patient who has undergone monthly follow-up visits that include clinical examination and videofibrolaryngoscopy, remains disease-free, 9 months after the histological diagnosis.

Discussion

Sarcomas are uncommon at laryngeal sites. In 1933, Figi ⁹ identified only 4 laryngeal sarcomas (0.55%) in an evaluation of 717 laryngeal neoplasms. RMSs are the most frequent sarcoma in paediatric patients, especially the embryonal and alveolar variants. They are much more infrequent in adults and represents only 3% of all sarcomas ³.

About 40% of RMSs are localized in the cervico-cephalic region ¹⁰ where, based on their location, three subtypes have been recognized: orbital, parameningeal and non-parameningeal. The orbital lesions have a better prognosis than those in other sites ¹¹. Non-parameningeal rhabdomyosarcomas can occur in the larynx and the larynx is affected in less than 3% of RMSs of the cervico-cephalic region ^4–10. The first case of laryngeal RMS was described by Glick in 1944 ¹², and only a few cases have been well documented since then ^13–17. In a number of case reports published on laryngeal RMS, the exact histology of the lesion has not been described and in only a few cases has their disease-free survival been charted ^{18 19} (Table I). In the last 10 years, only 6 cases of pleomorphic RMS of the larynx have been described. Akyol et al.²⁰ illustrated a case of pleomorphic RMS in a 68-year-old male; Ruske et al. ²¹ reported a case in a 66-year-old female; Prgomet et al. ²², in 2006, described another case of pleomorphic RMS of the vocal cord, Shayah et al. ¹³ reported a case of pleomorphic RMS in a 77-year-old female and, in 2007, Schrock et al. ¹⁴ described 2 cases of adult pleomorphic RMS. According to data in the literature, pleomorphic RMSs are less common than the other subtype ³, they are usually found in adults ³, while alveolar and embryonal varieties are more commonly encountered in children and adolescents ^{11 15 16}. Laryngeal pleomorphic RMSs are usually found more often in males than in females.

Table I. Case reports of laryngeal pleomorphic rhabdomyosarcoma.

N.	Year	Author	Age (yrs)/ sex	Treatment	FU	Status
1	1964	Filipo & Crifo*	53/M	Total laryngectomy, RT	8 m	NED
2	1970	Rodriguez & Ziskind 19	57/M	Total laryngectomy	?	?
3	1971	Laccourreye, et al.*	65/M	Total laryngectomy	41 d	DOD
4	1976	Frugoni & Ferlito 25	33/M	Subtotal laryngectomy, RT	6 y	NED
5	1977	Marasso, et al.*	65/M	RT + CHT	?	?
6	1977	Lamendola & Buonocore**	61/M	Total laryngectomy bilat. neck dissection	1 y	NED
7	1978	Winter & Lorentzen 18	72/F	Subtotal laryngectomy	?	?
8	1979	Seniukov, et al.*	55/M	Total laryngectomy, RT	4 m	NED
9	1979	Franz**	57/M	RT	2 y	NED
10	1987	Dodd-o, et al. 17	5/M	Total laryngectomy	18 y	NED
11	1988	De Agostino, et al.**	70/M	Total laryngectomy	?	?
12	1994	Jahnke & Vogl**	45/M	Total pharyngolaryngectomy, cervical oesophageal and tracheal resection, CHT + RT	?	?
13	1996	Da Mosto et al. 10	69/M	Total laryngectomy, RT	2 y	NED
14	1998	Akyol et al. 20	68/M	Total laryngectomy, neck dissection, RT	8 m	DOD
15	1998	Ruske et al. 21	66/F	Total laryngectomy, RT	30 m	NED
16	2006	Prgomet et al. 22		CO2 Laser cordectomy, CHT	6 y	NED
17	2007	Shayah et al. 13	77/F	Total laryngectomy	1 y	NED
18	2007	Schrock et al. 14	60/M	Total laryngectomy, neck dissection, RT, CHT	20 m	NED
19	2007	Schrock et al. 14	64/M	CO2 laser cordectomy, RT	20 m	NED
20	Our case	Pittore et al.	75/M	Partial laryngectomy	9 m	NED

^*Cited by Dodd-o et al.;

^**Cited by Da Mosto et al.

The clinical features and macroscopic laryngeal appearances do not differ substantially from the other malignant neoplasms, therefore histological and immunohistochemical studies are fundamental for correct diagnosis. Staining for vimentin indicates the mesenchymal origin, while the positivity for actin, desmin, myogenin and myoglobin indicates muscular differentiation ¹. Cytogenetic analysis can be especially helpful in the alveolar variant, which consistently shows the translocations t (2;13) (q35; q14) and t (1;13) (p36; q14), which code for the fusion oncoproteins PAX3-FKHR and PAX7-FXHR, respectively ¹. According to Grundy et al. ²³ and Garay et al. ¹, patients with alveolar RMS showing positivity for PAX3-FKHR have a poor prognosis.

RMSs are locally aggressive and have a tendency to metastasize by both the lymphatic and haematological routes (lung, liver, bone). Therefore, during follow-up, it is essential to plan for staging, imaging, including CT scans and standard thoracic radiographs. Nonetheless, RMS of the larynx is believed to be less aggressive than in other cervico-cephalic positions ^{17 24 25}.

Two methods for staging RMS are used. The initial staging system, adopted in the first 3 intergroup RMS studies, classifies patients on the basis of the extent of disease and the completeness of their initial surgical resection ^5–7 (Table II). In the IRS-IV the TNM ⁸ (tumour, node and metastasis) staging system (Table III) was used in association with the previous staging system.

Table II. Group staging system.

Group	Definition
I	Localized disease, completely resected
	a) confined to muscle or organ of origin
	b) contiguous involvement, with infiltration outside muscle or organ of origin; regional nodes not involved
II	Compromised or regional resection
	a) grossly resected disease with “microscopic residual”
	b) regional disease, completely resected, in which nodes may be involved and/or extend into an adjacent organ
	c) regional disease with involved nodes grossly resected, but with evidence of microscopic residual
III	Incomplete resection or biopsy, with gross residual disease
IV	Distant metastasis present at onset

Table III. TNM staging classification.

Stage	Sites	T	Size	N	M
1	Orbit, head and neck region (excluding parameningeal sites), or the non-bladder and/or non-prostate genito-urinary region	T1 or T2	a or b	N0 or N1 or Nx	M0
2	Bladder/Prostate, extremity, cranial parameningeal, other	T1 or T2	a	N0 or Nx	M0
3	Bladder/Prostate, extremity, cranial parameningeal, other	T1 or T2	a b	N1 N0 or N1 or Nx	M0 M0
4	All	T1 or T2	a or b	N0 or N1	M1

T1: Confined to anatomic site of origin: a) < 5 cm in diameter; b) > 5 cm in diameter; T2: extension and/or fixative to surrounding tissue: a) < 5 cm in diameter; b) > 5 cm in diameter; N0: lymph nodes not involved; N1: lymph nodes involved; Nx: unknown; M0: no distant metastasis; M1: metastasis present.

Based upon data in the literature, and especially in paediatric patients ^{11 26–33}, it would appear that optimal therapy for RMS is a multimodal approach comprising surgery followed by chemo- and/or radiotherapy. This was described in the Intergroup Rhabdomyosarcoma Studies (IRS) ^5–8. The IRSG, formed in 1972, included more than 4000 patients (< 21 years) with newly diagnosed RMS allocated to 4 protocol arms. Based on the results of this study, generally accepted treatment guidelines for childhood RMS include complete resection with preservation of function, chemotherapy and radiotherapy but the choice depends on a variety of disease factors (site, extent of lesion, etc.). Different combination agents were used including actinomycin-D (A), vincristine (V) and cyclophosphamide (C). The IRS-IV introduced the use of ifosfamide (I) + etoposide (E) with or without radiotherapy. The 3-year failure-free-survival (FFS) estimates remain unchanged from that of IRS-III⁸.

IRMS-V (study in progress) is using a new agent (topotecan) which has been shown to be particularly active in the treatment of alveolar RMS ⁸.

In a recent paper, Combs et al. ²⁷ showed the importance of post-operative radiotherapy in 19 paediatric patients with RMS located in the cervico-cephalic region, and reported a 5-year survival of 94%, and local control of disease in 89% of the cases. Thanks to these studies, 5-year survival rates have increased from 25%, in 1970, to 70% ⁸.

Several prognostic indicators have been identified which include age, tumour location, extension and histotype. Hawkins et al. ³ reported on a cohort of 84 patients with RMS and revealed better prognosis in patients aged < 20 years, tumour size < 5 cm, absence of loco-regional disease and radical surgical excision.

Wolden et al. ³⁴ revealed that certain characteristics were associated with significantly poorer FFS. These included, according to Hawkins et al. ³, tumours > 5 cm or with alveolar or undifferentiated histology. The final clinical factor affecting the patient’s prognosis is the extent of disease following initial surgical resection. As discussed by the Intergroup Rhabdomyosarcoma group (IRS-III and IRS-IV) ^{7 8}, patients without residual disease (Group I) have a 90% 5-year survival rate. In patients with microscopic residual disease (Group II), survival decreases to 80%, and those with gross disease after surgery (Group III) have a 5-year survival rate of 70%.

Conclusions

Laryngeal RMS is an extremely rare tumour which responds to surgery, but may also be treated by means of chemo-radiotherapy. However, further studies are needed in order to improve our understanding of its biological behaviour and to define the most appropriate therapeutic approach.