Leiomyosarcoma of the larynx: case report and review of the literature.

Abstract

Leiomyosarcoma of the larynx is an extremely rare entity. This tumor is aggressive and is associated with dismal treatment results. We present a case of leiomyosarcoma of the larynx treated with surgery and postoperative radiotherapy. In this article we also discuss laryngeal leiomyosarcoma's clinical manifestations, associated diagnostic dilemmas, and optimal management, as well as a review of the literature.

Introduction

Laryngeal leiomyosarcoma (LMS) was first described by Frank in 1941. (1) These are malignant smooth-muscle tumors originating from cutaneous and subcutaneous tissues, the extremities, genitourinary tract, gastrointestinal tract, and vascular walls. (2,3) Overall, the incidence of LMS is less than 10% of all soft-tissue sarcomas and is usually between 2.3 and 5.3% of malignant soft-tissue tumors in the head and neck region. (4,5) Primary sarcomas rarely occur in the larynx and account for a mere 0.3 to 1% of all laryngeal malignancies. (2,6) In one of the largest series of head and neck sarcomas, which included 352 patients, Freedman et al reported only 4 cases (1.1%) of LMS in the neck region. (7)

A thorough search of the MEDLINE and EMBASE databases revealed only 53 cases of laryngeal LMS reported to date. Because of the paucity of data, little information exists regarding optimal treatment modalities. The rarity of LMS often leads to a delayed clinical diagnosis, difficulty in establishing a histologic diagnosis, and confusion regarding its management. In this article we present a rare case of locally advanced LMS of the larynx and discuss this tumor's natural history, management, and the prognosis, as well as extensively reviewing the literature.

Case report

The patient, a 65-year-old man, presented to the Department of Otorhinolaryngology in February 2005 with complaints of hoarseness of 7 months' duration and breathlessness lasting for 3 months; the latter had progressed to stridor, necessitating an emergency tracheostomy. When the patient was evaluated the next day, endoscopy showed an ulceroproliferative growth involving the bilateral arytenoids, false vocal folds, and the laryngeal surface of the epiglottis.

Axial computed tomography (CT) showed a heterogeneously enhancing soft-tissue mass involving both the false and truevocal folds and extending to the supraglottis, arytenoids, and paraglottic space (figure 1).

An endoscopic biopsy was performed for tissue diagnosis. Histopathology revealed tumor cells arranged in fascicles and a storiform pattern (figure 2). The cells showed pleomorphism and nuclear atypia, with vesicular to hyperchromatic nuclei. These features were suggestive of LMS of the larynx. Sections were immunostained with the ABC (avidin biotin-peroxidase complex) method, with primary antibodies directed toward smooth-muscle actin (clone 1 A4), desmin (clone D33), neuron-specific enolase (NSE; clone H14), S-100 protein (polyclonal), and antihuman cytokeratin (clone 5D3). Immunohistochemistry (IHC) revealed mottled expression of smooth-muscle actin, while desmin, NSE, S-100 protein, and cytokeratin were negative. This confirmed the diagnosis of LMS.

The patient underwent total laryngectomy (TL) with partial pharyngectomy and hemithyroidectomy in February 2005. Perioperatively, a globular mass was observed arising from both false vocal folds, completely filling the glottis and extending to the arytenoids, supraglottis, and paraglottic space. Postoperatively, he underwent adjuvant radiation to the neck region at a dose of 45 Gy/20 fractions over a period of 4 weeks, which was completed in April 2005. He was disease-free at 10-month follow-up and remained disease-free 35 months post-treatment.

Review of the literature

A literature search was done using MEDLINE and EMBASE to identify cases of LMS of the larynx. The search was conducted in all document types, using the following MeSH terms: leiomyosarcoma AND larynx. The search produced 53 such cases; ours is case number 54. To the extent possible, we extracted data regarding patients' ages/sex, tumor sites, presenting symptoms, therapeutic methods, and outcomes. When full articles were not available, abstracts were used as the source of information. The table includes data derived from 31 of those cases for which abstracts or full articles were available in the English language, as well as the data from our case. The reviewed reports served as a source of information about LMS's clinical behavior, location, treatment, and overall prognosis.

According to Chen et al, the average patient age at presentation is within the fifth decade of life, with a male preponderance. (8) The average age at presentation of the patients whose data were derived from our literature review, plus our patient, was 58.3 years; 27 of 31 patients (87.1%) were male and only 4 of 31 (12.9%) were female (table). (The age and sex of 1 patient listed in the table are not known.)

The site at which LMS occurred was not reported for 1 patient whose data were included in the table. LMS was seen in the supraglottis in 5 of the remaining 31 patients (16.1%), while involvement of the glottis was seen in 15 of 31 (48.4%) patients; 2 patients had subglottic involvement, and 2 had transglottic involvement (6.5% each). Combined supraglottic-glottic involvement occurred in 4 of 31 patients (13.0%), and glottic-subglottic involvement occurred in 3 of 31 (9.7%) (table).

The clinical presentation of laryngeal LMS is diverse, and its severity depends upon the site, extent, and laterality of the tumor. (5) Presentation at the time of diagnosis can vary from mild symptoms such as hoarseness to life-threatening symptoms such as stridor. In our review, we found that 19 of 31 patients (61.3%) had hoarseness, 11 of 31 (35.5%) had dyspnea/respiratory distress and/ or stridor, 4 of 31 (12.9%) presented with dysphagia, and 4 (12.9%) presented with dysphonia (table). Most of the patients had overlapping symptoms.

[FIGURE 1 OMITTED]

Most of the patients whose data we compiled from the literature review (20 of 31 [65.5%]) underwent radical surgery in the form of TL; 10 of 31 (32.3%) had radiotherapy alone or as an adjuvant treatment following TL (table). Patients with subglottic LMS had a better prognosis.

Discussion

The incidence of LMS varies from 2.3 to 5.3% of malignant soft-issue tumors in the head and neck region. (5) The rarity of LMS in this region has been attributed to the scarcity of smooth muscle in the head and neck. The most common sites of involvement in the head and neck are the paranasal sinuses, scalp, cervical esophagus, and jaws. (9,10) Reports discussing the possible origin of LMS offer conflicting theories. Freiji et al, for example, have hypothesized that blood vessel smooth muscle is a possible site of origin, (11) whereas Chen et al have attributed the origin to aberrant mesenchymal differentiation and have raised the possibility that LMS might be metastatic rather than primary in origin. (8)

[FIGURE 2 OMITTED]

Histologically, LMS is comprised of fascicles of spindle cells with elongated "cigar shaped" blunt-ended nuclei. They are distinguished from leiomyomas (benign variant) by their characteristic malignant

properties (i.e., nuclear mitotic activity, hyperchromatism, and cellular pleomorphism. (9,12,13)

On light microscopy, the tumor shows interlacing bundles, or fascicles, of spindle-shaped cells with multinucleate pleomorphic nuclei. On first inspection this may, as in our case, initially be labeled as a spindle-cell tumor. However, when IHC studies are performed, the differences become more apparent. (13,14) Specific IHC stains, especially desmin, have helped to improve the accuracy of diagnosis and differentiate LMS from other mesodermal tumors, such as fibromas, fibrosarcomas, spindle-cell sarcomas, rhabdomyosarcoma, malignant melanomas, and inflammatory myofibroblastic tumors. (9,15) In most cases, IHC permits a reliable diagnosis of LMS.

The diagnosis of LMS is also supplemented by the following histopathologic features (15):

1. Presence of well-oriented, thin myofilaments (60 to 80 [Angstrom]) in a large portion of the cytoplasm, joined to the membrane by dense bodies;

2. Presence of pinocytic vesicles; and

3. Basal lamina encompassing all of the external membrane.

LMS mimics spindle-cell tumors or other sarcomas in metastasizing by a hematogenous route, mostly to the lung and liver (30 to 50%); regional lymphatic involvement tends to be a late phenomenon. The incidence of lymph node metastasis usually does not exceed 10 to 15%. (6,16)

Surgery remains the treatment of choice for LMS. Surgical options vary according to the site of the lesion and range from conservative procedures, such as microlaryngeal surgery (MLS), laser debulking, vertical partial laryngectomy (VPL), and simple partial laryngectomy (SPL), to aggressive procedures, such as TL. However, conservative surgeries such as MLS, laser debulking, VPL, and SPL have shown high recurrence rates, and hence are generally not recommended. Neck dissection is not recommended because of the lack of early lymph node metastasis, which has been substantiated by immunohistochemical and ultrastructural studies. (9)

Radiotherapy is primarily used adjuvantly in the postoperative period. The available evidence emphasizes the role of radiotherapy in reducing the risk of local recurrences. (17) Randomized trials for soft-tissue sarcomas of the extremities also have shown that radiotherapy has been effective in controlling local recurrences. (18-20) However, because of the small number of LMS cases, no randomized trials have been designed or published yet to show the effectiveness of adjuvant radiotherapy in head and neck LMS.

The survival statistics for head and neck LMS are inconclusive because of scarcity of data. Data collated from the literature have shown recurrence rates and 5-year survival rates of approximately 30 and 50%, respectively. (8,10) From the reviewed literature, it has been observed that subglottic LMS tends to have a better prognosis (table), while tumors larger than 5 cm and deep infiltrative tumors tend to have a poorer prognosis.

References

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(15.) Marioni G, Bottin R, Staffieri A, Altavilla G. Spindle-cell tumours of the larynx: Diagnostic pitfalls. A case report and review of the literature. Acta Otolaryngol 2003;123(1):86-90.

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(17.) Akcam T, Oysul K, Birkent H, et al. Leiomyosarcoma of the head and neck: Report of two cases and review of the literature. Auris Nasus Larynx 2005;32(2):209-12.

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(19.) Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16(1):197-203.

(20.) Suit HD, Mankin HJ, Wood WC, et al. Treatment of patient with stage M0 soft tissue sarcoma. J Clin Oncol 1988;6(5):854-62.

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(22.) Wolfowitz BL, Schaman A. Smooth-muscle tumours of the upper respiratory tract. S Afr Med J 1973;47(27):1189-91.

(23.) Kleinsasser O, Glanz H. Myogenic tumours of the larynx. Arch Otorhinolaryngol 1979;225(2):107-19.

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(28.) Helmberger RC, Croker BP, Mancuso AA. Leiomyosarcoma of the larynx presenting as a laryngopyocele. AJNR Am J Neuroradiol 1996;17(6):1112-14.

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Table. Literature review of published reports on leiomyosarcoma of
the larynx

Source                 Age/   Presenting    Symptom
                       sex    symptoms      duration

Eggston and            40/M   Hoarseness,   2 mo
  Wolf, (21) 1947             dyspnea

Wolfowitz and          60/M   Hoarseness    7 y
  Schaman, (22) 1973   35/M   Hoarseness    3 mo

Kleinsasser and        69/M   Hoarseness,   6 wks
  Glanz, (23) 1979            stridor

Levine and             28/F   Hoarseness,   3 y
  Tubbs, (24) 1986            dysphagia

Tewary and             56/M   Stridor       Few wks
  Pahor, (5) 1991

Chen                   69/M   Hoarseness,   6 wks
  et al, (8) 1991             stridor

Carles                 43/M   --            --
  et al, (25) 1992

Rowe-Jones             87/M   Dysphonia,    8 y
  et al, (26) 1994            aphonia

McKiernan and          28/F   Hoarseness    6 mo
  Watters, (27) 1995   43/M   Hoarseness    3 mo

Helmberger             87/M   Respiratory   8 mo
  et al, (28) 1996            distress,
                              dysphagia

Lippert                --     --            --
  et al, (29) 1997

Chae                   64/M   Hoarseness    6 mo
  et al, (30) 1999

Thomas                 72/M   Hoarseness,   2 mo
  et al, (14) 1999            stridor

Yoshizaki              81/F   Stridor,      --
  et al, (31) 1999            aspiration

Paczona                65/M   Hoarseness    8 mo
  et al, (32) 1999     31/F   --            Several mo

Cocks                  49/M   Hoarseness,   9 mo
  et al, (33) 1999            weight loss
                       78/M   Hoarseness    4 mo

Wadhwa                 62/M   Hoarseness    3 y
  et al, (10) 2000

Marioni                41/M   Dysphonia     9 mo
  et al, (9) 2000

Kainuma                79/M   Stridor,      1 mo
  et al, (37) 2001            dysphagia

Patrocinio             39/M   Snoring,      --
  et al, (34) 2002            stridor

Marioni                81/M   Dysphonia     3 mo
  et al, (15) 2003

Preti                  --     --            --
  et al, (35) 2003

Sasaki                 62/M   Hoarseness    --
  et al, (36) 2004

Akcam                  47/M   Hoarseness,   7 mo
  et al, (17) 2005            stridor,
                              dysphagia

Marioni                56/M   Dysphonia     7 mo
  et al, (13) 2005

Abbas                  65/M   Hoarseness    5 mo
  et al, (2) 2005

Skoulakis              74/M   Respiratory   --
  et al, (38) 2006            distress

Goda et al,            65/M   Hoarseness    7 mo
  2008 ([dagger])

Source                 Tumor                 Treatment(s)        RFS *
                       site(s)

Eggston and            TVF AC                TL                  18 mo
  Wolf, (21) 1947      (glottis)

Wolfowitz and          TG                    RT + TL             16 mo
  Schaman, (22) 1973   Right FVF (SPG)       VPL + RT            14 y
                                             [right arrow] TL

Kleinsasser and        Left FVF (SPG)        VPL + FND + RT      18 mo
  Glanz, (23) 1979

Levine and             LSE (SPG)             Excision +RT        18 mo
  Tubbs, (24) 1986

Tewary and             Right TVF,            TL                  3 y
  Pahor, (5) 1991      (glottis, SG)

Chen                   Left FVF (SPG)        VPL + FND + RT      18 mo
  et al, (8) 1991

Carles                 TVF, AC (glottis)     PL                  10 mo
  et al, (25) 1992

Rowe-Jones             Right TVF,            RT                  3 mo
  et al, (26) 1994     (glottis, SG)

McKiernan and          Right TVF (glottis)   MLS                 6 mo
  Watters, (27) 1995   B/L FVF AC            LD [right arrow]    6 mo
                       (SPG, glottis)        SPL

Helmberger             B/L, TVF, AC          TL                  30 mo
  et al, (28) 1996     (glottis)

Lippert                Left TVF (glottis)    C[O.sub.2]          >25 mo
  et al, (29) 1997

Chae                   Left TG               VPL [right arrow]   3 y
  et al, (30) 1999                           TL

Thomas                 SG                    LD [right arrow]    5 y
  et al, (14) 1999                           TL

Yoshizaki              Left TVF (glottis)    MLS [right arrow]   6 mo
  et al, (31) 1999                           TL

Paczona                Left TVF (glottis)    TL + MND            3 y
  et al, (32) 1999     TVF (glottis)         ELR                 22 mo

Cocks                  Right TVF             TL + RND + RT       3 mo
  et al, (33) 1999     (glottis, SG)
                       Right TVF,            MILS                22 mo
                       (glottis)

Wadhwa                 Right TVF, AC         TL + Right HT       3 mo
  et al, (10) 2000     (glottis)

Marioni                Right TVF, AC         MLS                 14 mo
  et al, (9) 2000      (glottis)

Kainuma                Right VF, SPG         TL + RT             10 mo
  et al, (37) 2001     (glottis)

Patrocinio             Right TVF             TL                  11 mo
  et al, (34) 2002     (glottis)

Marioni                Right TVF, AC         Laser VPL           7 mo
  et al, (15) 2003     (glottis)             [right arrow] TL

Preti                  --                    TL + RT             6 mo
  et al, (35) 2003

Sasaki                 Left SG               STL                 5 y
  et al, (36) 2004

Akcam                  Right VF, AC          TL + B/L FN D       21 mo
  et al, (17) 2005     (SPG, glottis)

Marioni                SPG, glottis          Cordectomy          5 mo
  et al, (13) 2005                           [right arrow] TL

Abbas                  Right TVF, AC         TL                  12 mo
  et al, (2) 2005      (glottis)

Skoulakis              Glottis               TL                  8 mo
  et al, (38) 2006

Goda et al,            B/L/ SPG              TL + PP + HT + RT   35 mo
  2008 ([dagger])

* Recurrence-free survival

([dagger]) Present study

Tumor sites: TVF = true vocal fold; AC = anterior commissure; TG =
transglottis; FVF = false vocal fold; LSE = laryngeal surface of
epiglottis; SG = subglottis; B/L = bilateral; SPG = supraglottis.

Treatments: TL = total laryngectomy; RT = radiotherapy; VPL = vertical
partial laryngectomy; FND = functional neck dissection; PL = partial
laryngectomy; MLS = microlaryngeal surgery; LD = laser debulking;
SPL = simple partial laryngectomy; C[O.sub.2] = C[O.sub.2] laser
surgery; MND = modified neck dissection; ELR = endoscopic laser
resection; RND = radical neck dissection; HT = hemithyroidectomy;
STL = simple total laryngectomy; Bx = biopsy; PP = partial
pharyngectomy.

Jayant Sastri Goda, MD, DNB; Karuppiah Saravanan, MS, DNB; R.K. Vashistha, MD, FRCPath; Vinay Kumar, MD; Ashok K. Gupta, MS

From the Department of Radiation Oncology (Dr. Goda and Dr. Kumar), the Department of Otorhinolaryngology (Dr. Sarvanan and Dr. Gupta), and the Department of Pathology (Dr. Vashistha), Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Corresponding author: Dr. Jayant Sastri Goda, MD, DNB, Senior Registrar, Department of Radiation Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, Section 12, PIN 160012, India. Phone: [phone]; fax: [phone]; e-mail: [e-mail]