Sarcomatoid Carcinoma of the Larynx: Immunohistochemical Analysis in Two Cases

The great majority of cancers encountered in the upper respiratory tract and oral cavity are squamous cell carcinoma (SCC), with only infrequent examples of other histologic variants. Lane1 introduced the term pseudosarcoma to describe oropharyngeal and laryngeal tumors that he believed were non-neoplastic stromal responses to an adjacent epidermoid carcinoma. This rare tumor has occasionally been termed pseudosarcoma (PS), carcinosarcoma, spindle cell carcinoma, or sarcomatoid carcinoma (SC). The 3 theories of the histogenetic nature of the spindle cell (Sc) component are: (1) it is not neoplastic, (2) it is the mesenchymal metaplasia of SCC, and (3) it is a true sarcoma. Recent evidence2 supports the concept that this tumor is a pleomorphic variant of SCC and not a benign connective tissue response. SCs are problematic lesions for the clinician as well as the pathologist. In the following presentation, to further investigate the nature of the Sc component, we present 2 cases of PS of the larynx studied by immunohistochemistry with cytokeratins (CKs), vimentin (VIM), desmin, and smooth muscle actin (SMA). A 63-year-old man presented with hoarseness of 2 months duration. The patient denied any dysphagia or otalgia and had a 20-pack year history of tobacco use. On videolaryngoscopic examination, there was a keratotic lesion on the right vocal cord extending from the vocal process to the anterior commissure. Vocal cord movement was normal bilaterally. Ultrasonography of the neck showed no lymph nodes. A direct laryngoscopy was performed, and the biopsy obtained was reported as SCC with sarcomatoid features. The patient was staged as T1N0M0. A right fronto-lateral laryngectomy was performed. Gross inspection of the right frontolateral laryngectomy specimen measuring 3.5 × 2.5 × 1 cm showed a 6 × 3 mm tumor mass attached to the anterior commissure, extending to the right true vocal cord. There was another polypoid mass measuring 5 × 3 mm distal to this lesion. The surface of the polypoid mass was ulcerated, other parts of the tumor appeared granular and white. The patient remains disease-free at 3 years. A 68-year-old woman complained of hoarseness and coughing of an unstated duration. A biopsy was performed at another center and the patient was referred to our department for further evaluation. The biopsy finding was SCC. Direct laryngoscopic examination revealed a fibrotic lesion of the left true vocal cord that extended to the ventricle. A three quarter laryngectomy and left functional neck dissection (FND) was performed. The laryngectomy specimen measuring 6 × 2 × 1.5 cm showed a 8 × 7 × 4 mm tumor filling the ventricle. The polypoid mass was ulcerated and the cut surface was gray-white. The left FND specimen with 20 lymph nodes did not show metastases. The patient is disease-free 30 months after the laryngectomy. Histologic and immunohistochemical (IHC) examinations were performed on tissues fixed in formalin. Histologic evaluation of the specimens was done by hematoxylin and eosin (H-E) stained slides on the whole mount specimens. Masson's trichrome and Weigert's reticulin stains were also performed to evaluate the stroma and the reticular background of the tumors. IHC studies of the tumor, which are summarized in Table 1, were performed with the streptavidin-biotin peroxidase procedure. Immunostaining was performed on paraffin-embedded tissues. Sections were cut 5 μm and mounted on poly-D lysine coated slides. The sources of the primary antibodies used, their working dilutions, and the method of the antigenic recovery are also summarized in Table 1. Counterstain was performed with Mayer's hematoxylin. Simultaneously, positive and negative controls were processed. Percentage of positive cells in the histologic specimens was assessed quantitatively. Specimens were considered immunopositive when ≥1% of the cells had clear evidence of immunostaining. The immunostaining intensity was semiquantitatively graded as absent, weak, moderate, or strong. The main tumor masses in both cases showed SCC with moderately to poorly differentiated features. Downward proliferation of the tumor cells created invasive masses with partly ulcerated surfaces. The tumors exhibited a tendency toward exophytic polypoid growth in the neighboring areas of the true vocal cord and ventricle (Fig 1). The area underlying the mucosal and ulcerated surface of these masses showed intercellular edema, stellate cellular outline, and some inflammatory infiltrate. The tendency of the blood vessels at the surface toward radial arrangement mimicked wound healing. The PS of these masses was primarly composed of malignant-appearing stellate or irregular spindle cells with large vesicular nuclei with prominent nucleoli (Fig 1). Many malignant and occasional benign-appearing touton-like tumor giant cells were observed. Moderate number of mitoses were noted. The cytoplasm was moderately plentiful and faintly eosinophilic. Keratinization and/or intercellular bridges were not found in this stroma. Few islands lands of SCC lying within the PS were observed. The transition from these islands to PS was abrupt, but some epithelial cells dropping off into the stroma were also observed. Thrichrome stain revealed various amounts of intercellular collagenous matrix, confirming the appearance in H-E stain. The Scs produced abundant reticulin enveloping the cells whereas areas of carcinoma did not. (A) Partly ulcerated polypoid mass near moderate to poorly differentiated SCC. (Hemotoxylin and eosin stain; original magnification X2.5.) (B) Malignant-appearing stellate or irregular spindle cells and tumor giant cells with large vesicular nuclei with prominent nucleoli within the PS. (Hemotoxylin and eosin stain; original magnification X2.5.) (C) Diffuse strong positivity for HMWCK in the islands of SCC trapped in PS. Note the abrupt transition from these islands to negative PS. (Peroxidase stain; original magnification X10.) Areas of conventional SCC reacted totally or partially with all of the anti-CK antibodies tested. The SCC revealed cells rich in high molecular weight CK (HMWCK), panCK and CK 19 (95% to 100%), whereas it was moderately poor in low molecular weight CK (20%). In SCC, only 1% of the cells were reactive with CK18 antibodies. Areas of SCC were negative for VIM, the PS of the tumors revealed tumor cells rich in VIM (95%), but showed no epithelial (Fig 1) or muscular (Desmin, SMA) expression. Diagnostic problems in SC include the difficulty in differentiating it from true sarcomas and from conventional SCC, and most importantly from granulation tissue. When the tumor involves the true vocal cords, it may clinically resemble a laryngeal polyp. Cancer may not be detected from small biopsies. Sarcomatoid carcinoma is an epithelial malignancy in which the majority of the sarcoma-like Scs are believed to be variants of the epithelial cells. Saphir and Vass3 concluded that these tumors were carcinomas, imitating sarcomas. Lane1 in 1957, proposed the term pseudo-sarcoma for carcinomas with sarcomatous features. Electron microscopy demonstrated the fibroblast as the predominant cell in the stroma. The second stromal cell type was a type of histiocyte.4 In this study, the PS was absolutely negative for all antibodies against CKs in both cases, even in the epithelial-like cells, dropping off into the PS from islands of SCC. Broad amount of cells (95%) within the PS expressed VIM but showed neither epithelial nor muscular features. Our results did not show any IHC evidence that these cells are positive for CKs. The islands of SCC trapped in PS showed diffuse strong positivity for HMWCK and panCK but were either negatively stained for CK18 and CK19 or weakly positive in the interface between SCC and PS. Some investigators not finding epithelial properties in sarcomatoid areas as we did, concluded that these were benign stromal reactions.4 The fact that not all SCs show detectable epithelial differentiation is not viewed as a contraindication to the diagnosis of SC. This study demonstrates the SC component is not muscle in origin, as judged by negative staining for Desmin and SMA. The survival reports of the patients with SC support that the PS is not a malignant mesenchymal component of the tumor. The prognosis of this tumor is similar to that of SCC without associated pseudosarcoma. Aside from invasion, histologic features and gross configuration were not found to be of significant prognostic importance.5 Patients with early stage SC of the glottis treated with radiation had similar control rates as irradiated patients with similar volume of disease with more typical SCC. There are conflicting statements on the metastatic potential of the polypoid SC tumors of the larynx.2 Functional neck dissection in case 2 did not show any metastatic disease. We believe that in a conventional SCC, for various reasons, the tumor mass is destroyed and replaced by the reparative tissue composed of Scs. Few foci of uninjured tumor tissue and exaggerated reparative activity create a polypoid mass that in turn results in early symptoms of laryngeal pathology and surgical intervention and creates good prognosis. Both of the patients are still alive with no evidence of disease 3 years after their surgeries, which is the course expected from a conventional SCC, rather than a sarcoma, with a more favorable prognosis. Sarcomatoid carcinoma of the upper aerodigestive tract continues to be one of the most difficult diagnostic challenges for surgical pathologists. The results of this study have led us to conclude that IHC examination is of value in the diagnosis of SC. As is shown in the present article along with the literature, the SC is a SCC with spindle-shaped sarcoma-like reparative activity in polypoid configuration that grows in an IHC spectrum of epithelia and mesenchyme. The reason why certain rare cases of laryngeal carcinoma develop such a bizarre mesenchymal reaction is yet to be clarified.