ARTICULO CLÍNICO

Introduction

Spindle cell carcinoma is a malignant variant of squamous cell carcinoma that is very rare.^1-4 It is characterized by the simultaneous proliferation of malignant epithelial cells and spindle cells of a sarcomatous type, and it is thus considered a biphasic tumor.^1-3,5-7 This type of growth has generated various hypotheses as to its origin and behavior, which is reflected in the varied terminology used for designating it: spindle cell carcinoma, pseudosarcoma, carcinosarcoma, pseudosarcomatous squamous cell carcinoma, sarcomatoid carcinoma, metaplastic carcinoma, pleomorphic carcinoma, spindle cell squamous carcinoma^.7-11

Currently it is thought to have an epithelial origin,^1,4 although some authors are still dubious about this.^12-14 It can be found in any part of the epithelium of the body, although it is most commonly found in the upper aerodigestive tract, larynx and oral cavity. More rarely it is to be found in the skin, esophagus and paranasal sinuses.^{1,2,8,9,15,16}

Material and method

The object of this work is to carry out a descriptive study of these cases describing the clinical behavior while trying to understand the pathogeny behind the controversial lineage of this tumor.

Results

With regard to tumor stage, two cases were classified as stage I (T₁N₀M₀), three as stage II (T₂N₀M₀) and four as stage IV (three as T₄N₀M₀ and one as T₂N_2bM₀).

There were a total of 12 cases of tumor recurrence in five out of the nine patients, most with squamous cell carcinoma as a primary neoplasm. In three cases there was an initial recurrence in the form of squamous cell carcinoma and later in the form of spindle cell carcinoma. In one patient there was an initial recurrence in the form of spindle cell carcinoma followed by two later recurrences in the form of squamous cell carcinoma. The most common location was on the floor of the mouth (50%), followed by the tongue (34%). The treatment of choice for these recurrences was surgical. Only one patient that was initially diagnosed with spindle cell carcinoma experienced local tumor recurrence in the form of squamous cell carcinoma.

Discussion

Spindle cell carcinoma is a rare malignant neoplasm that mainly affect males (male: female ratio 4-10:1) between the age of 50 and 70 according to the different studies.^1-5,17-20 In our series we did not find this relationship (1.25:1). It is of relevance that no risk factor was found among the women.

Spindle cell carcinoma is made up of two cellular types: the epithelial component tends to be in a minority and the histological image varies between dysplasia and squamous cell carcinoma.^5,7,17-19 There tends to be little or no evidence of keratinization.⁴ The principal component is sarcomatous^2,6,18 and, on occasions, transitional areas between both cellular types can be identified.^5-8,17,18 (Figs. 1, 2 and 3). Heterologous osteo-, chondro- or rhabdomyosarcomatous elements can appear^17,19 that are associated with previous radiotherapy.¹⁷ Among the factors related to a predisposition that are recorded in the literature are cigarette and alcohol consumption, bad oral hygiene, exposure to the sun^{1,8-10,15,17,19-21}, radiations^7-9,17,19-21 and previous trauma.^1,4 Likewise, it has been observed that this tumor is to be found more commonly on skin scars that are secondary to burns.^1,4 A case in conjunction with an odontogenic cyst has also been described.²² This is in agreement with the results observed in our series, in which the most important risk factors are tobacco and alcohol. We have found a high incidence of leukoplasia in these cases, a fact that was not reflected in the bibliography referred to.

The prognostic factors include deep invasion of the tumor,^{2,19,20,21,23,24} location,^{9,18,23,25,26} metastasis to cervical lymph nodes,^{9,18,20,25,26} tumor size^9,18,19 and the carcinomatous component, 12 TPI (correlation with survival), degree of differentiation,^18,19 keratin positivity,¹⁹ staging²³ and tumor morphology.²⁶

It tends to appear as an exophytic, polypoidal quicklygrowing mass, with an ulcerated surface, and more unusually it will appear as a sessile, nodular or endophytic mass.^{2,4,6,8-10,17-19,25} It is associated with aggressive clinical behavior^{5,8,9,15,23,26} if it has, fundamentally, an intraoral location,^10,21 and it appears in previously irradiated patients. It has a strong tendency to metastasize more commonly to the lymph nodes, or distantly.^2,4,8 Batsakis y cols²⁵ (1981) presented 111 cases of spindle cell carcinoma of the upper aerodigestive tract, and they reported a rate of lymphatic metastasis of 24%. Other series found lymphatic metastasis in up to 50% of cases.²⁷ These metastases can be epithelial, sarcomatoid or mixed.^{2,6,8,9,19,28} There is a high rate of local recurrence. ^{8,17,21,27,28} The mortality rate is high and it varies between 24 and 90% depending on the authors.^17,21,25

The origin of this tumor has been very controversial over the last years. There are various theories as to its genesis. The first was put forward by Lane¹² in 1957. This author believes that it is a benign reaction in response to an adjacent squamous cell carcinoma. Sherwin¹⁴ (1963) believes that it is a combination of a reactive benign reaction and a variant of squamous cell carcinoma, while Minckler¹³ (1970) supports the theory that it is in fact a true sarcoma. Leventon²¹ and Zarbo²⁹ consider that the tumor originates from a pluripotential stem cell that could exhibit both mesenchymal and epithelial differentiation, and they have even suggested that the sarcomatous component represents a metaplastic alteration of the spinocellular component,¹ thus the name carcinosarcoma. Ellis and cols¹⁶ (1987) believe that the tumor originates from epithelial cell loss during keratin expression, thus the name spindle cell carcinoma.

Currently, the theory that is most accepted is the one that points to an epithelial origin.^10,18,21 Supporting this theory is the histological observation of a transition within the tumor itself, of the squamous component to a spindle one. In our series we found various cases of this transition, of squamous cell carcinoma to spindle cell carcinoma as well as the reverse. Histological and ultrastructural studies show the conservation of epithelial differentiation markers in spindle cells, of cytokeratins^{2,3,6,7,11,15,17,18,23,26} as well as of tonofilaments, desmosomes and keratohyaline aggregates.^4,7,18,20,23 Likewise, Lauwers and cols¹⁸ (1998) published a series of 13 cases of fusocellular carcinoma of the esophagus in which 12 (95%) showed cytokeratin positivity.

In 1996, Thompson and cols.³⁰ were able to show genoand phenotypic similarities between both cellular types by means of a DNA study. It has been demonstrated that in both cell lines there is a common disturbance in the expression of the supressor gene p53^6,7 as well as in cyclin D1 (a cell-cycle regulator),²⁴ which suggests that both disturbances play a role in the molecular pathogenesis of this tumor, and they support the idea of a common origin. Ansari-Lari and cols⁷ confirm the monoclonal origin of the neoplasm on showing inactivation patterns of the X chromosome and identical chromosome aberrations.

Slootweg and cols¹¹ (1989) related the expression of keratin with the cellular phenotype. In this respect they observed that in two cases of squamous cell carcinoma that recurred as spindle cell carcinoma there was a lower expression of this protein, while in one case of spindle cell carcinoma that recurred as squamous cell carcinoma, the expression was higher. Based on the retrospective observation in our series we believe that the origin of this tumor is epithelial.

Now that the epithelial origin of the neoplasm has been accepted, the most recent studies endeavor to find out the disturbances that occur on a molecular level. Epithelial cells express cytokeratin, e-cadherin (intercellular adhesion molecule), alpha- and beta-catenins (molecules of cell cytoplasm) ¹ and EMA (epithelial membrane antigen),² while spindle cells preferably express vimentin (a marker of sarcomatous cells), and the expression of cytokeratins and E-cadherin is diminished.^{1,2,6,11,15,17,26} It is thought that the reduction or loss of E-cadherin as well as the heterogeneous expression of alpha- and beta-catenins are responsible for the loss of intercellular adhesion, which will lead to the cellular morphology changing from squamous to spindle shape. This permits a growth pattern that is more diffuse and infiltrative, thus explaining the aggressiveness and metastasis of this tumor.^1,2,6,18 In the literature referred to, there is agreement on all spindle cells expressing vimentin, and a variable percentage of these express citokeratin,^{1,2,6,11,15,17} which leads us to believe that the morphological change experienced by the cellular lineage could be influenced by the expression of these and other molecules from membranes as well as from cytoplasm.

Lauwers and cols¹⁸ (1998) found that the sarcoma-like zones had areas that were more aneuploid than the carcinomatous zones, and there was more biological activity, with the TPI (Tumoral Proliferative Index) registering by means of immunoreactivity, values of 0.44 for squamous areas and 0.68 for spindle areas. They report, in addition to this, a different DNA pattern, as low ploidy zones were found in squamous areas and low and high ploidy areas in spindle areas. This indicates a more aggressive clinical behavior. ⁶

Conclusions

Spindle cell carcinoma is a rare variety of squamous cell carcinoma and it is thought to have an epithelial origin. It is found more commonly in the upper aerodigestive tract. It shows aggressive behavior and the rate of regional metastasis is not to be despised. Histological diagnosis is complicated, and resorting to immunohistochemical techniques and electron microscopy is often necessary.

Acknowledgments

To Dr. Ferreras Granado for the help and interest shown in the preparation of this article.

Dirección para correspondencia
C/ Almirante Mourelle 29 2º
15011 La Coruña, España
E-mail: guis@canalejo.org

Recibido: 15.02.2005
Aceptado: 23.01.2006

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