Keywords
larynx - sarcoma - chondrosarcoma - leiomyosarcoma - liposarcoma - undifferentiated
pleomorphic sarcoma
Introduction
Laryngeal neoplasms are divided into epithelial and nonepithelial tumors based on
their origin.[1]
[2] Epithelial tumors comprise the majority of laryngeal neoplasms, and squamous cell
carcinoma is the most common malignant neoplasm of the larynx.[1]
[2]
[3] Nonepithelial tumors are much less common. This category includes sarcoma, melanoma,
and lymphoma. Primary laryngeal sarcomas are rare and account for less than 1% of
laryngeal tumors.[1]
[2]
[3]
[4]
[5] They are classified based on their phenotype and histological grade, similar to
their soft tissue counterparts. However, the clinical presentation, treatment, and
prognosis of laryngeal sarcomas are different.[1]
[2]
[3]
[4] There are few studies of laryngeal sarcomas reported in the literature.[1]
[2]
[3]
[4]
[5] Despite that, information regarding the clinical features, biologic behavior, and
treatment modalities of laryngeal sarcomas is still limited. Herein, we describe an
additional four cases of different pathologic types of laryngeal sarcomas, to increase
awareness and understanding about these rare tumors, to avoid potential diagnostic
pitfalls.
Case Presentation
Case 1
A 49-year-old male presented to the emergency department with difficulty in breathing
and weight loss for 3-month duration, exacerbated by physical activity. Fiberoptic
examination revealed a subglottic fleshy soft tissue mass obstructing 80% of the upper
airway. Computed tomography (CT) scan of the neck revealed a soft tissue mass lesion
in the infraglottic region at the left side of cricoid and arytenoids cartilage, protruding
inside the lumen and compromising the airway ([Fig. 1A]). The patient underwent total laryngectomy with left hemithyroidectomy. Macroscopic
examination of the resected specimen revealed a submucosal ill-defined tan lobulated
mass, occupying the left thyroid laryngeal cartilage that measured 2.9 × 2.5 × 2 cm.
Microscopic examination showed a tumor composed of lobules of hyaline cartilage permeating
into the adjacent bony trabeculae. The tumor showed mild increase in cellularity as
well as cytological atypia, in the form of nuclear hyperchromasia and occasional binucleation
([Fig. 1B] and [C]). The diagnosis of low-grade chondrosarcoma was rendered. The resection margin was
free of the tumor. Postoperative course was uneventful. Five months later, there was
no evidence of tumor recurrence or metastasis by imaging studies.
Fig. 1 Radiological and microscopic features of low-grade chondrosarcoma. (A) Computed tomography scan of the neck demonstrates a lesion in the infraglottic (red
arrow). (B) Photomicrograph shows lobule of neoplastic hyaline cartilage (hematoxylin and eosin
[H&E] stain, 100x). (C) High-power view demonstrates increased cellularity, and mild nuclear atypia, (H&E
stain, 400x).
Case 2
A 57-year-old male patient presented with hoarseness of voice for one-year duration.
A glottic mass arising from the right vocal cord was found by fiberoptic examination.
CT scan of the neck showed thickening at the glottic anterior commissure, with focal
submucosal nodular intense enhancing lesion ([Fig. 2A]). The patient underwent right anterior cordectomy and debulking of the glottic mass.
Macroscopic examination of the resected specimen revealed multiple tan/white irregular
rubbery and friable soft tissue fragments, measuring 3 × 1.5 × 0.5 cm. Histopathological
examination showed a submucosal tumor composed of fascicles of moderately atypical
spindle cells with abundant eosinophilic cytoplasm, marked nuclear pleomorphism, and
prominent hyperchromasia. Brisk mitotic activity was noted ([Fig. 2B] and [C]). The tumor cells were strongly and diffusely reactive for smooth muscle actin (SMA)
([Fig. 2D]) and calponin, but negative for keratin AE1/AE3, keratin MNF 116, keratin ⅚, desmin,
MyoD1, myogenin, S100, and Melan A. Based on these findings, the diagnosis of leiomyosarcoma
was made. The resection margin was free of the tumor. Two weeks after the surgery,
the patient noticed improvement of his voice. Ten months later, there was no evidence
of recurrence or metastasis by imaging studies.
Fig. 2 Radiological, microscopic, and immunohistochemical features of leiomyosarcoma. (A) Computed tomography scan of the neck demonstrates thickening at the glottic anterior
commissure, with focal submucosal nodular lesion (red arrow). (B) Photomicrograph shows submucosal fascicles of moderately atypical spindle cells
(hematoxylin and eosin [H&E] stain, 100x). (C) High-power view shows moderately atypical spindle cells proliferation (H&E stain,
400x). (D) The tumor cells demonstrate diffuse, strong cytoplasmic, and membranous reactivity
for smooth muscle actin.
Case 3
A 36-year-old gentleman presented to the outpatient clinic with difficulty of breathing
and swallowing for 3-month duration. Fiberoptic examination revealed a smooth mobile
swelling arising from the right hypopharyngeal wall causing partial airway obstruction.
CT scan of the neck revealed a lesion along the posterior wall of the hypopharynx
([Fig. 3A]). Macroscopic examination of the resected specimen revealed a nodular rubbery lesion
measuring 3.5 × 3 × 1.5 cm. Microscopic examination showed a submucosal tumor composed
of lobules of atypical spindle cells in a prominent myxoid stroma with arborizing
chicken-wire vasculature. Other areas showed lobules of adipose tissue separated by
thick fibrous septa that contains atypical hyperchromatic spindle cells ([Fig. 3B] and [C]). By immunohistochemistry, the tumor cells were reactive for CDK4 ([Fig. 3D]). By fluorescence-in-situ-hybridization (FISH) analysis, MDM2 gene amplification was detected along with amplification of DDIT3 probe region. Based
on the immunohistochemistry and cytogenetics results, the diagnosis of well-differentiated
liposarcoma (WDL) with prominent myxoid stroma was rendered. There was no evidence
of tumor recurrence or metastasis detected by magnetic resonance imaging performed
6 months later.
Fig. 3 Radiological, microscopic, and immunohistochemical features of well-differentiated
liposarcoma. (A) Computed tomography scan of the neck shows a well-defined lesion along the posterior
wall of the hypopharynx (red arrow). (B) Photomicrograph shows lobules of adipose tissue separated by thick fibrous septa
containing atypical hyperchromatic spindle cells (hematoxylin and eosin [H&E] stain,
40x). (C) High-power view shows atypical hyperchromatic spindle cells in a prominent myxoid
stroma with arborizing chicken-wire vasculature (H&E stain, 200x). (D) The tumor cells demonstrate nuclear staining for CDK4.
Case 4
A 59-year-old ex-smoker, male patient presented with hoarseness of voice, stridor,
and shortness of breath for 3 months duration. Fiberoptic examination revealed no
obvious masses. CT scan of the neck showed a heterogeneous enhancing laryngeal mass,
partially obstructing the upper airway ([Fig. 4A]). The patient underwent total laryngectomy with bilateral neck dissection. Macroscopic
examination of the resected specimen showed a tan-white irregular mass, located at
the glottis, involving the left true vocal cord, and extending to the midline that
measures 1.5 × 0.8 × 0.7 cm. Microscopic examination showed extensive infiltration
by a malignant neoplasm, composed of pleomorphic and bizarre spindle cells, interspersed
by numerous histiocytes ([Fig. 4B] and [C]). Marked mitotic activity was identified, including atypical forms. A wide panel
of immunohistochemical stains was performed, all of which were negative except vimentin.
CD68 was reactive in the histiocytic population. Based on these findings, the diagnosis
of undifferentiated pleomorphic sarcoma was rendered. The tumor was completely excised.
One month later, radiotherapy was initiated. He was followed up at 6- and 12-month
intervals and there were no signs of recurrence or metastasis.
Fig. 4 Radiological and microscopic features of undifferentiated pleomorphic sarcoma. (A) Computed tomography scan of the neck demonstrates a heterogeneous enhancing laryngeal
lesion (red arrow). (B) Photomicrograph demonstrates submucosal malignant spindle cell neoplasm (hematoxylin
and eosin [H&E] stain, 100x). (C) High-power view shows pleomorphic and bizarre spindle tumor cells (H&E stain, 400x).
Discussion
Laryngeal neoplasms are divided into epithelial and nonepithelial tumors.[1]
[2] The vast majority of laryngeal tumor are carcinomas, and squamous cell carcinoma
is the most common histologic type.[1]
[2]
[3]
[4]
[5] Nonepithelial tumors constitute approximately 5% of all laryngeal neoplasms that
include sarcoma, lymphoma, and melanoma.[1]
[2]
Laryngeal sarcomas account for less 1% of laryngeal neoplasms.[1]
[2]
[3]
[4]
[5] Various sarcoma types have been reported to occur in the larynx. Their nomenclature
and classification are similar to their soft tissue counterpart. However, there are
considerable differences between laryngeal sarcomas and soft tissue sarcomas. The
former presents early and are diagnosed at earlier stage. Thus, laryngeal sarcomas
have lower mortality and less rate of local recurrence and distant dissemination.[1]
[2] In addition to that, negative margins are difficult to achieve in laryngeal sarcomas
due to the anatomical complexity of the region. Moreover, laryngeal tumors are removed
in piecemeal in some cases, which impose diagnostic challenge for the pathologist
examining the specimen.
There is wide variation in the histomorphologic features of laryngeal sarcomas. Chondrosarcoma
is the most common primary sarcoma of the larynx.[1]
[6]
[7]
[8] It has been found that the conventional subtype is the most common; however, other
subtypes such as clear cell, mesenchymal and dedifferentiated chondrosarcomas have
been reported.[6]
[7]
[8] More than 50% of cases arise in association with chondroma component, which makes
the diagnosis of low-grade chondrosarcoma more challenging.[1]
[6]
[7] Tumor cellularity and nuclear atypia are useful features to differentiate chondroma
from low-grade chondrosarcoma, the latter is more cellular, and the chondrocytes demonstrate
nuclear atypia in the form of hyperchromasia and irregular nuclear contours with frequent
binucleation. Extensive sampling of the tumor is necessary to detect any dedifferentiated
component, which is characterized by the presence of high-grade spindle cell sarcoma
adjacent to the low-grade component.[1]
[6]
[7] Up to 50% of laryngeal chondrosarcomas develop local recurrence, and the risk increases
with incomplete excision.[6]
[7] However, they have very low risk of distant metastasis.[6]
[7] Therefore, conservative surgery with preservation of the laryngeal function and
obtaining negative margins is advocated. In the largest cohort study of laryngeal
chondrosarcoma, they found that it has an excellent prognosis with relatively high
5- and 10-year survival rates (88 and 66%, respectively).[8]
Leiomyosarcoma of the larynx is much less common.[1]
[9] It most commonly arises from the glottic and supraglottic regions.[1]
[9] It is essential to rule out the possibility of sarcomatoid carcinoma before making
the diagnosis of leiomyosarcoma. Immunohistochemical stains are useful in this setting;
sarcomatoid carcinomas are reactive for high molecular weight keratin, p63 and p40.
On the other hand, leiomyosarcoma would be negative for these antibodies, but positive
for smooth muscle markers such as smooth muscle myosin, desmin, and caldesmon.[10] Another important feature that helps to distinguish sarcomatoid carcinoma is the
presence of dysplasia in the overlying surface squamous epithelium. Patients with
laryngeal leiomyosarcoma have been found to be at increased risk for distant dissemination[11] therefore, surgical resection with negative margins, in addition to adjuvant chemotherapy,
should be considered.[9]
[10]
Liposarcomas of the larynx are usually well-differentiated, either in the form of
lipoma-like or sclerosing subtypes.[12] It is essential to differentiate WDL from lipoma and its variants, such as spindle
cell and pleomorphic lipoma. The presence of lipocytes of variable sizes, thick fibrous
bands that traverse the tumor, and atypical hyperchromatic spindle cells are features
that favor WDL. In some cases, with limited tissue material, the diagnosis is difficult
to achieve on hematoxylin and eosin stain. In such cases, the use of MDM2 and CDK4
by immunohistochemistry and/or FISH is helpful to establish the diagnosis.[13]
[14] Positive staining for MDM2 and/or CDK4 or the detection of their amplified genes
by FISH confirms the diagnosis of WDL.[13]
[14] It is also essential to extensively sample the tumor to rule out the possibility
of dedifferentiated liposarcoma, which is characterized by the presence of high-grade
spindle cell sarcoma adjacent to the well-differentiated component.[12] It has been found that up to 50% of laryngeal liposarcomas recur; therefore, the
current recommendation is to perform wide surgical excision with negative margins.[1]
[12]
Undifferentiated pleomorphic sarcoma (UPS) is a rare laryngeal tumor that arises most
commonly from the glottis.[15] It is a diagnosis of exclusion that is made after running a wide panel of immunohistochemical
stains and ancillary studies. Sarcomatoid carcinoma is essential to exclude, which
is usually positive for high molecular weight keratin, p63 and p40. Dedifferentiated
liposarcoma is another possibility that should be considered and ruled out by running
MDM2 and CDK4 through immunohistochemistry or FISH. UPS/MFH is an aggressive tumor
with high rate of local recurrence and metastasis[16]
[17]
[18] therefore, wide surgical excision and obtaining negative margins are recommended.[17] Adjuvant radiotherapy and/or chemotherapy may be considered in large tumors and
patients with positive margins.[16]
In summary, we describe an additional series of four cases of primary laryngeal sarcoma
([Table 1]), which adds on more information about this rare category of laryngeal tumors. The
perplexity of resection of laryngeal tumors and difficulty to achieve negative margins
may impose a diagnostic challenge. Correct identification of the histomorphologic
features, and awareness of the various subtypes of laryngeal sarcomas, is essential
to guide the treatment plan that is tailored for patients in tumor boards.
Table 1
Summary of the clinicopathological features of the primary laryngeal sarcomas
|
Low-grade chondrosarcoma
|
Leiomyosarcoma
|
Well-differentiated liposarcoma
|
UPS
|
|
Age (years)/gender
|
49/Male
|
57/Male
|
36/Male
|
59/Male
|
|
Presentation
|
Difficulty in breathing and weight loss
|
Voice hoarseness
|
Difficulty in breathing and swallowing
|
Voice hoarseness, stridor, and SOB
|
|
Tumor location
|
Subglottis
|
Glottic anterior commissure
|
Posterior wall of the hypopharynx
|
Glottis and left true vocal cord
|
|
Tumor size (cm)
|
2.9 × 2.5 × 2 cm
|
3 × 1.5 × 0.5 cm
|
3.5 × 3 × 1.5 cm
|
1.5 × 0.8 × 0.7 cm
|
|
Treatment modality
|
Total laryngectomy with left hemithyroidectomy
|
Right anterior cordectomy and debulking of the mass
|
Mass excision
|
Total laryngectomy with bilateral neck dissection and radiotherapy
|
|
Margin status
|
Negative
|
Negative
|
Positive
|
Negative
|
|
Recurrence
|
No recurrence
|
No recurrence
|
No recurrence
|
No recurrence
|
|
Follow-up (months)
|
5 months
No recurrence or metastasis.
|
10 months
No recurrence or metastasis.
|
6 months
No evidence of local recurrence or definite metastatic neck lymph nodes noted on MRI
neck
|
12 months
No recurrence or metastasis
|
Abbreviations: MRI, magnetic resonance imaging; SOB, shortness of breath; UPS, undifferentiated
pleomorphic sarcoma.
Declaration
Two cases were published previously separately as case reports. The undifferentiated
pleomorphic sarcoma case was published under the title “Glottic Malignant Fibrous
Histiocytoma: A Case Report and Literature Review” (Aljariri AA, Alsaleh AR, Al-Enazi
HA, Haider HA, Petkar M, Rahman W, Nashwan AJ. Glottic Malignant Fibrous Histiocytoma:
A Case Report and Literature Review. Case Rep Oncol. 2021 Mar 31;14(1):641–646. doi:
10.1159/000514977. PMID: 33976647; PMCID: PMC8077659). The WDL case was published
under the title “Well-Differentiated Liposarcoma of the Hypopharynx Exhibiting Myxoid
Liposarcoma-like Morphology with MDM2 and DDIT3 Co-Amplification” (Murshed KA, Abo
Samra H, Ammar A. Well-Differentiated Liposarcoma of the Hypopharynx Exhibiting Myxoid
Liposarcoma-like Morphology with MDM2 and DDIT3 Co-Amplification [published online
ahead of print, 2021 Jun 4]. Head Neck Pathol. 2021;10.1007/s12105-021-01341-5. doi:10.1007/s12105-021-01341-5).
