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Spindle cell carcinoma of the oral cavity
Spindle cell carcinoma of the oral cavity A clinicopathologic Gary L. Ellis, D.D.S.,* ARMED TRAINING
FORCES
INSTITUTE
CENTER,
assessment of fifty-nine cases Washington, D.C., and Russell L. Corio, Captain (DC) USN** OF PATHOLOGY
WASHINGTON,
AND
VETERANS
ADMINISTRATION
DENTAL
D.C.
The clinical features, histomorphologic characteristics, therapeutic results, and follow-up data for fifty-nine cases of spindle cell carcinoma of the oral cavity were analyzed. Circumstantial evidence favors a pathogenesis from metaplastic malignant epithelial cells for the spindle cell proliferation. These neoplasms occurred most frequently on the lower lip, tongue, and alveolar ridge in either polypoid, exophytic, or endophytic configurations. A male predominance was attributed to a military and veteran bias. Mean age at occurrence was 51 years for men and 67 years for women. Symptoms were infrequently reported. Histomorphologically, fasciculated, myxomatous, and streaming patterns of the spindle cells were observed, with variable mitotic activity, pleomorphism, benign and atypical giant cells, inflammation, vascularity, and infiltration. Follow-up data on forty-five patients revealed that only fourteen were alive and well, whereas twenty-five were dead of their disease. Mean survival time for those dead of the disease was under 2 years. Five-year survival was a significant indicator of cure. No clinical or histomorphologic characteristic other than distant metastasis was found to be a reliable prognostic indicator. Wide surgical excision, alone or with radical neck dissection, was the most successful therapeutic modality. Radiation was ineffective.
ncommon, peculiar, bimorphic tumors, which U have been the subject of considerable controversy within the literature, occur mainly in the upper respiratory and alimentary tracts. Histologically, these tumors, which usually are polypoid in configuration, are composed of surface epithelial changes varying from mild epithelial dysplasiato invasive carcinomain associationwith, and usually dominated by, an abundant dysplastic-appearingspindle-cell component. The controversy concerns the pathogenesisof the spindlecell element and its related clinical, therapeutic, and prognosticbehavior. It has beenconfusingly reportedas carcinomatous,‘-l4 sarcomatous,15-l7 and reactive.18-22 Diagnostic terms, such as spindle cell carcinoma, carcinosarcoma, and pseudosarcoma, reflect this divergence of interpretation. Unfortunately, however, these terms have sometimesbeen applied indiscriminately. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, the Department of the Navy, or the Department of Defense. *Staff, Veterans Administration Dental Training Center, and Department of Oral Pathology, Armed Forces Institute of Pathology. **Vice-Chairman, Deparhnent of Oral Pathology, Armed Forces Institute of Pathology.
Virchow has been credited with the introduction of the term carcinosarcoma to describe neoplasmswith both epithelial and mesenchymal maIignant constituents.l, ’ Certainly, many of the early reports of carcinosarcomawere probably based solely upon the observationof a sarcoma-likeproliferation in combination with carcinomatous elements. In 1938 Saphir and Vass’published an extensive analysis of 153 casesof carcinosarcomareported in the literature, including twenty-two oral, laryngeal, and esophagealtumors. They concluded that most were neither collisions nor combinationsof sarcomasand carcinomasbut were actually carcinomaswith spindling features. More recent reports,15-17however, have reaffirmed the concept of dual malignant head and neck mucosal neoplasms. Proponentsof carcinosarcomahave sited the independent metastasisof the sarcomatousand carcinomatous components and electron microscopic evidence of mesenchymaldifferentiation to support their position. In 1957 Stout and Lattes18and Lane’” independently reportedcasesof polypoid biphasic tumors-Stout and Lattes reporting on tumors of the esophagusand Lane reporting on those of the larynx, fauces, and mouthand proposedthat the sarcoma-liketissues in these lesions were bizarre but nonneoplasticreactive connective tissue responsesto overlying squamouscell carci523
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Oral Surg. December, 1980
Table I. Vital statistics of fifty-nine cases of spindle cell carcinoma of the oral cavity Sex Male Female
40 19
4s 29-93 yr. 56.6 yr. 51.5 yr. 67.2 yr.
Range Mean Male Female Race White Black Other Not specified Fig. 1. Clinical photographof an exophytic, polypoid lesion of the gingiva and alveolar mucosa with a hemorrhagic appearance.(AFIP Neg. 80-135.)
nomas. They used the termpseudosarcoma . In defining the spindle cell portions as benign, Lanelg noted that there was no transition from carcinomatous to sarcomatoid elements. He observed that the squamous carcinomas were well differentiated in contrast to the pleomorphic spindle cell proliferations and that the sarcomatous elements did not metastasize. His special stains revealed spindle cells enveloped by connective tissue fibers, and he noted that some cases had apparent clinical cures as a result of what he considered inadequate treatment for sarcoma. Subsequent reports20-22 have supported the concept of pseudosarcoma presented by Lane. The majority of oral, laryngeal, and esophageal mucosal spindle cell tumors reported in the literature have favored an epithelial derivation. In 1919 Kettle,23 in one of the earliest reports, advanced the concept that carcinoma cells could assume the morphologic characteristics of mesenchymal cells. Even earlier, Krompecker was reported to have espoused the idea that epithelial cells, under certain conditions, may actually be transformed into mesenchymal cells.23 While this latter idea has not been generally adopted, it has received recent support. l2 Interestingly, foci of osseous and cartilagineous metaplasia have been reported within spindle cell carcinomas. 5*s* 16,24Proponents of a carcinomatous pathogenesis have almost universally cited histologic evidence of transition from epithelial cells to spindle cells. Ultrastructural analysis by electron microscopy has not resolved the pathogenetic dilemma. Goellner and colleagues*l have suggested that the spindle cell component of these bimorphic tumors consists of nonneoplastic histiocytic and fibroblastic cells. Minckler and co-workers’5 and Martin and Kahn” have concluded from electron microscopic studies that the spindle ele-
43 1 3 12
Table II. Anatomic location of fifty-nine cases of spindle cell carcinoma of the oral cavity and follow-up data Anatomic sire
of cases
Died of disease
Alive and well
Lower lip Tongue Alveolar ridge or gingiva Floor of mouth Antrum Retromolar/tonsillar pillar Buccal mucosa Upper lip Hard palate
25 12 II 3 2 2 2 1 1
10 4 3 2 2 2 0 1 1
9 1 4 0 0 0 0 0 0
No.
ments were malignant fibroblasts. On the other hand, Leifer and colleagues9 found, by electron microscopy, that the cells were mesenchymal in appearance but epithelial in origin. Battifora12 reported electron microscopic evidence of the actual transformation of epithelial cells into mesenchymal cells. On the basis of anultrastructural analysis, Shields,8 Someren,r3 Lichtiger,’ and Osamura14 and their associates all supported an epithelial origin for the spindle cell component. It is not our intent to unequivocally prove or disprove any of the histogenetic hypotheses; however, it would seem prudent to attempt to correlate the histomorphologic features with the clinical features and biologic behavior of a series of these bimorphic lesions. A few series of cases from the larynx and esophagus have been reported. ** 5, lo, 11,*l, 25Of these, Hyams’rO study of thirty-nine laryngeal lesions was the most extensive. Brooks26 reported on 110 cases from areas throughout the body but did not elaborate on specific numbers of cases or the biologic behavior of lesions from oral, pharyngeal, or laryngeal sites. Only a small number of oral mucosal lesions have been reported,3B 4, ‘* g, l*, 13, 19, 24, 27-30 and four cases make up the largest series.3’‘, ls In order to give greater definition to these
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of an exophytic,polypoidspindlecell carcinomawith ulceratedsurface. Fig. 2. Low-powerphotomicrograph (Hematoxylinandeosinstain. Magnification,x2. AFIP Neg. 80-522.) Table Ill. Symptoms in twenty-three patients with spindle cell carcinoma of the oral cavity Svmptom Swelling Pain Nonhealing ulcer Dysphagia Hemorrhage Loose teeth
Table IV. Clinical features in patients with spindle cell carcinoma of the oral cavity
No. of patients 7 7 5 2 I 1
biphasic malignant neoplasms, we have reviewed the clinicopathologic characteristicsof fifty-nine “spindle cell carcinomas” of the oral and maxillary sinus mucosa that were submitted for consultation to the Armed Forces Institute of Pathology. MATERIALS AND METHODS
The files of the Armed Forces Institute of Pathology (AFIP) include casematerial submitted by pathologists from military, Veterans Administration, and civilian sources. This sNdy was based on fifty-nine selected casesfrom material submitted to the AFIP for consultation. Requirementsfor inclusion in the study were (1) origin of the lesions in the maxillary sinus or oral mucosa, defined as extending from the vermilion borders of the lips to the tonsillar fauces; (2) adequateclinical information and histologic material available for review; and (3) histologic demonstration of epithelial
NO.
Died oj
of cases disease Size of lesion (cm) Range Mean Duration Range Mean Growth configuration Exophytic Endophytic Not specified History of prior irradiation
0.5-5.0 2.1 2.0
22 22
5 days-4 yr. 9.5 mo.
35 35
10
30 25 4 13
12 10 3 4
changes ranging from prominent dysplasia to frank squamous cell carcinoma in conjunction with a dysplastic spindle cell elementor evidenceof direct transition of epithelial cells to dysplastic spindle cells. Follow-up information was obtained on forty-five of the fifty-nine cases. The standard hematoxylin and eosin stain was employed in all cases, with randomly selected casesinvestigated by one or more of the following special stain techniques: Masson trichrome, phosphotungstic acid-hematoxylin (PTAH), Fontana melanin, reticulum, and periodic acid-Schiff (PAS) with and without prior diastasedigestion.
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Flg. 3. Spindle cell carcinoma of the lower lip exhibiting an exclusively endophytic growth configuration. (Hematoxylin and eosin stain. Magnification, X2. AFIP Neg. 77-2538.)
RESULTS Clinical features
Sex, age, race, and location. Over all, a two-to-one male-to-femaleratio was recorded(Table I). However, when only the thirty-eight casesfrom civilian sources were considered, there were twenty-one male and seventeenfemale patients, indicating the male bias expected of casesfrom military and VeteransAdministration hospitals. Ninety-one percent of the patients whose race was noted were Caucasian(Table I). At the time of diagnosis, the patients’ages ranged from 29 to 93 years, with a mean age of 57 years. Interestingly, the mean age for women (67 years) was much higher than that for men (50 years), as shown in Table I. Although lesions occurred in sites throughout the oral cavity (Table II), the lower lip was by far the most frequentsite of occurrence(twenty-five cases).Next in frequencyof occurrencewere the tongue(twelve cases) and the alveolar ridge or gingiva (Fig. 1) (eleven cases). Symptoms. Symptoms were recorded in only twenty-threecases(Table III). Swelling and pain were the two principal symptoms most often documented. Nonhealing ulcer, dysphagia, hemorrhage,and loose teeth were additionalcomplaints.The interval from the onsetof symptomsuntil diagnosis(Table IV), recorded in thirty-five cases,rangedfrom 5 days to 4 yearswith
a mean of 9% months. Particularly noted in several cases,however, was a suddenrapid increasein the size of the tumor. Thirteen patients had a history of prior therapeutic irradiation to the region where a spindle cell tumor subsequentlydeveloped.The time interval from irradiation to diagnosis of spindle cell carcinoma ranged from 1.5 to 10 years, with a mean of 6.9 years. No significant findings as to personalhabits, such as smoking, alcohol intake, or occupation,of the patients could be gainedfrom the available information. Gross pathologic features. The commonly reported polypoid, exophytic growth configuration(Figs. 1 and 2) was manifestedin thirty cases,but a sessile,nodular, or endophytic configuration (Fig. 3) was present in twenty-five cases(Table IV). In four casesthe clinical presentationwas unknown. Tumor size (Table IV), recordedin twenty-two cases,varied from 0.5 to 5.0 cm. in greatestdimension, with a mean of 2.1 cm. These tumors were most often describedas ulceratedbut firm and without central necrosis. Histopathologic
features
More than 93 percentof the lesionsin this serieshad a usually extensivelyulceratedsurfacecoveredwith an eosinophilic fibrinonecrotic material (Fig, 2). While this necrotic surface layer was of variable thickness, foci of necrosis within the central portions of the
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Fig. 4. Carcinoma in situ of the oral mucosal surface epithelium (right) adjacent to proliferating spindle cells, which composed the bulk of the lesion. A diffuse, mononuclear, inflammatory cell infiltrate is present. (Hematoxylin and eosin stain. Magnification, ~63. AFIP Neg. 80-524.)
Fig. 5. Moderately dysplastic mucosal surface squamous epithelium (top and left) with apparent transition of the basal cells to spindle cell elements. (Hematoxylin and eosin stain. Magnification, X 100. AFIP Neg. 80-525.)
tumors were rare. This latter finding may be related to the prominent vascularity that the majority of these tumors displayed. The vascular&y was usually most prominent immediately subjacent to the layer of surface necrosis. Despite the vascularity, hemorrhage within the lesions was observed only occasionally.
As a requirement for inclusion in this study, all cases showed either foci of squamous cell carcinoma or evidence of dysplasia of the mucosal epithelium (Fig. 4). This epithelium usually composed a minor portion of the tumor mass and was found mostly within the stalk or periphery of the lesion. Sometimes multiple sections
528 Ellis and Corio
Oral Surg. December, 1980
Fig. 6. Groups of pleomorphic spindle-shapedcells with parallel axes arrangedin an intersecting, fasciculated pattern. (Hematoxylin and eosin stain. Magnification,
X 100. AFIP Neg. 80-526.)
Fig. 7. Spindled and stellate cells with prominent intercellular spaces producing a less cellular, more myxomatous appearancethan the fasciculatedpattern. There is a prominent inflammatory cell infiltrate. (Hematoxylin and eosin stain. Magnification, x 100. AFIP Neg. 80-531.)
were r(squired before it could be demonstrated. In some lesionsi no surface epithelium was present on the sections savailable for study, but foci of poorly to welldiffere ntiated squamous cell carcinoma were found within the spindle cell tumor mass. In those cases which revealed only mild to moderate epithelial dysplasia, there was required evidence of proliferation of
basal cells with transition to spindle cell elements. This transition or “dropping-off” phenomenon was observed in many tumors (Fig. 5). The dysplastic spindle cell components usually constituted the greatest portions of the tumors and presented varied histomorphologic features. Tissue patterns could be categorized as fasciculated, myxcama-
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Fig. 8. Markedly pleomorphic spindle, stellate, and giant cells in a noncohesive,nonoriented,so-calledstreaming pattern. (Hematoxylin and eosin stain. Magnificatip, x 100. AFIP Neg. 80-530.)
Fig. 9. Both benign-appearing,mul&tcleated, foreign body type giant cells (right) and atypical tumor giant cells wlth multiple pleomorphic nuclei (left) were seenwithin the spindle cell componentof thesetumors. (Hematoxylin and eosin stain. Magnification, x403. AFIP Neg. 80-133.)
tous, or streaming. A fasciculated pattern (Fig. 6), the most common of the patterns, was composed of highly cellular groups of elongated bipolar cells in parallel alignment with the fascicles interwoven. The cell nuclei were elliptical and vesicular, and each contained
one or more nucleoli. A variable number of rounded cells with more abundant cytoplasm and round vesicular nuclei were scattered among the elongated cells. The less cellular myxomatous pattern (Fig. 7) showed prominent intercellular spaces, with the cells more
530 Ellis and Corio
Oral Surg. December, 1980
Fig. 10. Osteoidformationin a tumor from the mandibularalveolarridge. (Hematoxylinand eosin stain. Magnification,x 100.AFIP Neg. 80-527.)
pleomorphic and stellate in form than in the fasciculated pattern. The nuclei were more sphericalbut were still vesicularwith conspicuousnucleoli. The streaming pattern (Fig. 8) was depicted by moderately cellular groups of spindle and pleomorphic cells arrangedin randomly orientedcords and sheetswithout notableintercellular edemaspacesor interweavingfascicles. Although one tissue pattern was often dominant within a tumor, most lesions presenteda combination or spectrumof histologic patterns.In general, cellular and nuclear pleomorphismwere more prevalentin the myxomatous and streaming patterns, but all patterns exhibited wide variation. Likewise, the number of mitotic figures, a significant feature, was quite variable, even from focus to focus within an individual tumor. Mitoses ranged from one per ten high-power fields to five per high-power field. Becauseof the cellular density, tumors with a fasciculatedpattern tended to have a larger number of mitoses per high-power field but not necessarilymore per numberof cells observed. Multinucleated giant cells were a common finding within the spindle cell component (Fig. 8). Both benign-appearinggiant cells of the foreign-body type and bizarre, pleomorphicatypical giant cells were seen (Fig. 9). In addition, acute and chronic inflammatory cell infiltrates, mild to moderatein intensity, were frequently dispersedthroughoutthe spindle cell elements (Figs. 4 and 7). Special stains confirmed that the supportingstroma of most tumors was scant and varied from fibrillar to
densely collagenous.In four cases, all involving the mandibularalveolarridge or gingiva, osteoidformation within the dysplastic spindle cell componentwas observed (Fig. 10). Neither intracytoplasmiccross striations nor melanin pigment could be demonstratedby special staining techniques. Infiltration of subjacentstructures, such as skeletal muscle, bone, salivary glands, and nerves, by spindle cells was exhibited in thirty-two cases.While involvement of thesedeep structureswas more frequently observed in tumors with an endophytic configuration, it was often seenin exophytic lesions as well. Tissue from metastatic foci was available for histologic study in six cases; the tissue was taken from four cervical lymph nodesand two pulmonarylesions. In four casesthe metastaseswere composedof spindle cell elementsonly, while in two casesthe metastases contained squamouscell carcinomatousand spindle cell “sarcomatous”elementstogether(Fig. 11). The initial interpretationby thirty of the contributing pathologists was carcinoma. Twelve others classified their lesionsas sarcoma,most commonly fibrosarcoma. Undifferentiatedmalignant neoplasmwas the submitted diagnosisin two cases, and benign fibrous lesion was the diagnosisin five cases.No opinion was expressed in ten cases. Therapy and follow-up data
A generalcharacterizationof methodsof therapyand their results is given in Table V. Follow-up data were
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Fig. 11. A cervical lymph node which contains metastaticfoci of both ‘‘carcinomatous”(right) and “sarcomatous” (left) elements. (Hematoxylin and eosin stain. Magnification, ~63. APlP Neg. 80-134.)
obtained in forty-five of the fifty-nine cases (Table VI). Fifty-five percent of these patients were dead of their disease, and only 31 percent were alive without evidence of residual or recurrent tumor. Three patients died of other causes without evidence of having the study disease, and two patients had tumors but died of unrelated causes. One patient was alive with the disease. The mean follow-up interval (Table VII) for those patients still alive and well was less than 5 years. The mean survival time of those patients dead of the disease was 1.9 years. Documentation of recurrent tumor was noted in twelve cases, and metastasis was noted in sixteen. The cervical lymph nodes were the most frequent site of metastasis (eleven cases). Four of seven patients with cervical lymph node metastasis alone and all nine patients with distant metastases were known to have died of their disease (Table VIII). The death rate was not influenced by tumor size, gross configuration, or a prior history of irradiation (Table IV). While the prognosis was not good for spindle cell carcinomas arising in any oral location, those whose tumors occurred on the lower lip had the best survival rate (Table II). Although each lesion in the series was classified as to predominant tissue pattern and subjectively quantified as to amount of pleomorphism, mitotic activity, number of giant cells, extent of inflammatory infiltrates, and amount of hemorrhage and necrosis, no histomor-
Table V. Therapy in fifty-nine cases of
spindle cell carcinoma of the oral cavity and follow-up data NO. Therapy Surgery Surgery with RND*
Radiation Surgeryand radiation Surgerywith RND* and radiation Chemotherapy Not specified
of cases
Died of disease
Alive and well
5
1 2
5
41
12 3
7 It
3 0 3 1
I
I
0
6
3
1
21
6
* RND = Radicalneckdissection. t One additionalpatienthad the study diseasebut died of other causes. phologic characteristics were found to be more prominent or to occur more frequently in tumors from patients who died of their disease than in tumors from patients who were alive and well. DISCUSSION
Whether these biphasic neoplasms of the oral cavity represent a squamous cell carcinoma associated with an atypical, benign, reactive connective tissue process (pseudosarcoma), a combination or collision growth of a carcinoma and a sarcoma (carcinosarcoma), or a squamous cell carcinoma with a peculiar spindle ccl
532 Ellis and Corio
Oral Surg. December, 1980
Table VI. Follow-up data on forty-five patientswith
spindle cell carcinomaof the oral cavity Status
No. of patients
Alive and well Alive with disease Dead of disease Dead of other causes Dead of other causeswith disease
14 1 25 3 2
TaMe VII. Follow-up interval for forty-five patients with spindle cell carcinomaof the oral cavity
All patients Patients alive and well Patientsdeadof disease
Range
Mean
1 mo.-I 1 yr. 8mo.-11 yr. 1 mo.-6 yr.
3 yr. 4.5 yr. 1.9yr.
Table VIII. Follow-up information on casesof spindle cell carcinomaof the oral cavity: Recurrencesand metastases
Recurrences Metastases* Cervical lymph nodes Lung Heart Skin Bone
No. of cases
Dead of disease
12 16 11 6 1 1 1
7 13 8 6 1 1 1
*Four patientshad both cervical lymph node and distant metastases.
anaplasia(spindlecell carcinoma)is a questionof more than academicinterest. Prognosisand treatmentdepend upon the conceptof pathogenesisadopted. Evidenceof local and distant metastasisof the spindle cell element,documentedin six casesin this series, and an over-all deathrate of forty-two percent(55 percent of the patientswith follow-up) would seemto preclude an interpretation of a benign reactive process. Conversely, the independentmetastasisof “sarcomatous” elementsand a high deathrate lend supportto the concept of carcinosarcoma.However, certain features argue againstcarcinosarcoma.First, areasof transition of basal squamousepithelial cells to spindle cell forms were common histologic observationsin thesetumors. Battifora12haspresentedelectronmicroscopicevidence of modulation of cellular characteristicsfrom epithelial, to epithelial and mesenchymaltogether,to mesenchymal. Second, lymphatic spreadwas the most frequent metastatic pathway, the predominant route of carcinomas.Sarcomasmore often embolize via blood
vessels.31Third, the averageage at occurrencecorrelated with that for squamouscell carcinomaof the oral mucosa.32Finally, although these lesions are uncommon, the simultaneousoccurrence of epithelial and mesenchymalmalignant neoplasmsat the same site would seem to be distinctly rare. Electron microscopicstudieshave proved contradictory, with various reports interpreting the spindle elements as benign mesenchymal, malignant mesenchymal, and malignantepithelial.7-g,12-15* I’, 21From the largest seriesstudied by electron microscopy (thirteen cases), Lichtiger and colleagues7concludedthat the spindle cell component was carcinomatous in nature. Although the evidence is circumstantial, we subscribe to the conceptthat thesebimorphic tumors of the oral cavity representa variant of squamouscell carcinoma, and we prefer the term spindle cell carcinoma. Analysis of this series of fifty-nine casesindicated that thesetumorsoccurredmost frequentlyon the lower lip, tongue, and alveolar ridge of Caucasianmen of middle age and older. The male preferencewas nearly eliminated when only casesfrom civilian sourceswere evaluated.Previousreports have indicateda male predominance.5,‘, lo* l1 Unexplainedwas the significantly older mean age at occurrencein women. On the lip most tumors had a endophytic growth configuration, while in other locations most lesions were exophytic. Tumors in the larynx and esophagushave been reported to cause hoarseness,dysphagia, and obstruction,5. loa11,33but few of the casesof oral lesionsin this seriesrecordedany symptoms.Pain and swelling were the symptomsmost often noted. Of the forty-five patients on whom follow-up data were obtained, only fourteen were alive and without evidenceof disease,and only six of thosefourteenhad been followed for 5 years or longer. When the three patientswho died of other causeswere not considered, the survival rate was 36 percentwith follow-up periods ranging from 8 months to 11 years. That figure was lower than previously reported for spindle cell carcinorna’O*l1 but was consistentwith that for squamous cell carcinomaof the oral mucosa32 and that reportedby Appelmanand Oberman5for spindle cell carcinomaof the larynx. The meansurvival time following treatment for the twenty-five patients who died of their disease was less than 2 years; therefore, a 5-year survival would seemto be significantly indicative of cure. Certain clinical features of spindle cell carcinoma have previously been implicated as having prognostic significance.A polypoid, exophyticgrossconfiguration has been thought to have a better prognosisthan a sessile, endophytic configuration.4-g*13*34In this series, however, forty percent of the patients with exophytic
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tumors and 40 percentof the patients with endophytic lesions succumbedto their disease.Randall and associates,” who reportednine casesfrom the larynx, and Brooks,2”who reviewed 110 casesfrom many locations, stated that the size of the tumor was the only reliable indicator of prognosis.In the current study the mean size of tumors in patients who died of their disease was actually fractionally smaller than the mean size of all lesions. It has also beenreportedthat therapeutic irradiation to the site of subsequentappearance of a spindlecell carcinomawas a contributingetiologic facto+ i. 9, XJ*2i and that the prognosiswas worse in such cases.:]A history of prior radiation was documentedin thirteen casesin this review of oral spindle cell carcinomas.A thirty percent death rate for these patientssuggestedthat a history of radiationwas not an important prognosticfactor. Radiation may have been an etiologic factor. As would be expected, metastasissignaled a very poor prognosis.In this study 81 percentof the patients with recordedmetastasisdied of their disease.All nine patientswith known metastasesof distant organsdied. In an attemptto correlatethe histopathologicfeatures of spindle cell carcinomawith prognosis,the features of lesionsfrom patientswho died of their diseasewere comparedto the over-all incidence or prominenceof such features.The predominanttissuepattern (fasciculated. myxomatous, or streaming), degree of pleomorphism, numberof m itotic figures, number of giant cells, amount of inflammatory cell infiltrate, presence of hemorrhageand necrosis,and extent of invasioninto subjacenttlssue structureswere evaluatedand found to be neither significantly more nor less prominent in tumors that resultedin the deathof the patient. Formation of osteoid-appearingmaterial within the spindle cell componentwas found in four cases, all occurring on the alveolar ridge. This finding lead to speculationthat theselesionsmay have beenosteosarcomas arising from the periosteumor alveolar bone. However, these tumors met all the criteria for spindle cell carcinoma as previously defined. Osteoid and chondroid material have been reported in spindle cell carcinomasof the larynx5 and in lymph node metastasesfrom spindlecell carcinomasof the tongueg3 24and larynx. I6 Although the prognosisfor spindlecell carcinomaof the oral cavity was not good, surgical intervention, with or without radical neck dissection, resulted in a better survival rate than radiation alone or a combination of radiation and surgery. In this seriesfollow-up datarevealedthat nine of eighteenpatientstreatedwith surgery alonewere alive and well. However, only four of eighteen patients treated with radiation, alone or with surgery, were alive and without disease.These
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results are in agreementwith Hyams”O finding, in a study of thirty-nine spindle cell carcinomas of the larynx, that radiation therapy was ineffective. Chemotherapy was employed in only one case in our series, and the patientdied of the disease.The value of radical neck dissectioncould not be determined.
REFERENCES 1. Saphir, O., and Vass, A.: Carcinosarcoma,Am. J. Cancer33: 331-361, 1938. 2. Frank, I., and Lev, M.: Carcinosarcomaof the Larynx, Ann. Otolaryngol (Paris) 49: 113-129, 1940. 3. Greene,G. W., Jr., and Bemier, J. L.: Spindle-Cell Squamous Carcinomaof the Lip; Report of Four Cases,ORAL SURG. 12: 1008-1016, 1959. 4. Sherwin, R. P., Strong, M. S., and Vaughn C. W., Jr.: Polypoid and Junctional Squamous Cell Carcinoma of the Tongue and Larynx With Spindle Cell Carcinoma (“Pseudosarcoma”), Cancer 15: 51-60, 1%3. 5. Appelman, H. D., and Oberman, H. A.: SquamousCell Carcinoma of the Larynx With Sarcoma-Like Stroma: A Clinicopathologic Assessmentof Spindle Cell Carcinoma and “Pseudosarcoma,” Am. J. Clin. Pathol. 44: 135-145, 1965. 6. Himalstein, M. R., and Humphrey, T. R.: Pleomorphic Carcinoma of the Larynx, Arch. Otolaryngol. 87: 389-395, 1968. I. Lichtiger, B., Mackay, B., and Tessmer, C. F.: Spindle Cell Variant of SquamousCarcinoma: A Light and Electron Microscopic Study of 13 Cases,Cancer 26: 1311-1320, 1970. 8. Shields, T. W., Eilert, J. B., and Battifora, H.: Pseudosarcoma of the Esophagus,Thorax 21: 412479, 1972. 9. Leifer, C., Miller, A. S., Putong, P. B., and Min, B. H.: Spindle Cell Carcinoma of the Oral Mucosa: A Light and Electron Microscopic Study of Apparent SarcomatousMetastasisto Cervical Lymph Nodes, Cancer 34: 59’7-605,1974. 10 Hyams, V. J.: Spindle Cell Carcinoma of the Lwjnx, Can. J. Otolaryngol. 4: 307-313, 1975. 11 Randall, G., Alonso, W. A., and Ogura, J. H.: Spindle Cell Carcinoma(Pseudosarcoma)of the Larynx. Arch. Otolaryngol. 101: 63-66, 1975. 12 Battifora, H.: Spindle Cell Carcinoma:Ultrastructural Evidence of SquamousOrigin and Collagen Production by the Tumor Cells, Cancer 37: 2275-2282, 1976. 13 Someren, A., Karcioglu, Z., and Clairmont. A. A.: Polypoid Spindle Cell Carcinoma(PleomorphicCarcinoma): Report of a CaseOccurring on Tongue and Review of the Literature. ORAL SURG. 42: 47449, 1976. 14. Osamura, R. Y,, Shimamura, K., Hata, J., et al.: Polypoid Carcinoma of the Esophagus: A Unifying Term for “Carcinosarcoma”and “Pseudosarcoma,” Am. J. Surg. Pathol. 2: 201-208, 1978. 15. Minckler, D. S., Meligro, C. H., and Norris, H. T.: Carcinosarcoma of the Larynx: -CaseReport With M&stases of Epidermoid and SarcomatousElements, Cancer 26: 195-200, 1970. 16. Staley, C. J., Ujiki, G. T., and Yokoo, H.: “Pseudocarcinoma” of the Larynx: IndependentMetastasis of Carcinomatousand SarcomatousElements, Arch. Otolaryngol. PQ:458-465, 1971. 17. Martin, M. R., and Kahn, L. B.: So-Called Pseudosarcomaof the Esophagus:Nodal Metastasesof the Spindle Cell Element, Arch. Pathol. Lab. Med. 101: 604-609, 1977. 18. Stout, A. P., and Lattes, R.: Tumors of the Esophagus.In Atlas of Tumor Pathology, Sect. 5, Fast. 20, Washington, D. C.. 1957, Armed Forces Institute of Pathology, pp. 95-103. 19. Lane, N.: Pseudosarcoma(Polypoid Sarcoma-LikeMasses)AssociatedWith SquamousCell Carcinomaof the Mouth, Fauces. and Larynx: Report of Ten Cases,Cancer 10: 19-41, 1957. 20. Enrile, F. T., DeJesus,P. O., Bakst, A. A., and Baluyot, R.: Pseudosarcomaof the Esophagus (Polypoid Carcinoma of
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21. 22. 23. 24. 25. 26. 27. 28.
Ellis and Corio Esophagus With Pseudosarcomatous Features), Cancer 31: 1197-1202, 1973. Goellner, J. R., Devine, K. D., and Weiland, L. H.: Pseudosarcoma of the Larynx, Am. J. Clin. Pathol. 59: 312-326, 1973. Miller, D.: Pseudosarcoma of the Larynx, Can. J. Otolaryngol. 4: 314-318, 1975. Kettle, E. H.: On Polymorphism of the Malignant Epithelial Cell, Proc. R. Sot. Med. 12: l-32, 1919. Willis, G. W.: Metastatic Metaplastic Carcinoma From a Pseudosarcoma (Lane Tumor) of the Mouth, South. Med. J. 70: 1467-1468, 1977. Pearlman, S. J.: So-Called Carcinosarcoma of the Esophagus, Ann. Otolaryngol. (Paris) 49: 805-820, 1940. Brooks, S. M.: Carcinoma Which Simulates Sarcoma: A Study of 110 Specimens From Various Sites, Arch. Pathol. 36: 144157, 1943. Martin, M. R., and Stewart, F. W.: Spindle Cell Epidermoid Carcinoma, Am. J. Cancer 24: 273-298, 1935. Mittehnan. G. J.. Pickle, D. E.. Scoou. I. W.. and Greene. G. W., Jr:: Spindle Cell Carcinoma ofthe Floor of the Mouth; ORAL SURG. 20: 399406, 1965.
Oral Surg. December. 1980 29. Gelfman, W. E., and Williams, A.: Spindle-Cell Carcinoma of the Tongue: Report of a Case, ORAL SIJRG.27: 659-663, 1969. 30. Snyder, M. B., Myers, J., and Steinberg, A. J.: Polypoid Squamous Carcinoma of the Floor of the Mouth, ORAL SURG. 38: 763-768, 1974. 31. Robbins, S. L.: Pathologic Basis of Disease, Philadelphia, 1974, W. B. Saunders Company, p. 120. 32. Shafer, W. G., Hine, M. K., and Levy, B. M.: A Textbook of Oral Pathology, ed. 3, Philadelphia, 1974, W. B. Saunders Company, pp. 11 l-120. 33. Matsusaka, T., Watanabe, H., and Munetomo, E.: Pseudosarcoma and Carcinosarcoma of the Esophagus, Cancer 37: 1546-1555, 1976. 34. Davies, D. G.: Fibrosarcoma and Pseudosarcomaof the Larynx, J. Laryngol. 83: 423-434, 1969. Reprint requests to: Dr. Gary L. Ellis Armed Forces Institute of Pathology Washington, D. C. 20306
FORCES
INSTITUTE
CENTER,
assessment of fifty-nine cases Washington, D.C., and Russell L. Corio, Captain (DC) USN** OF PATHOLOGY
WASHINGTON,
AND
VETERANS
ADMINISTRATION
DENTAL
D.C.
The clinical features, histomorphologic characteristics, therapeutic results, and follow-up data for fifty-nine cases of spindle cell carcinoma of the oral cavity were analyzed. Circumstantial evidence favors a pathogenesis from metaplastic malignant epithelial cells for the spindle cell proliferation. These neoplasms occurred most frequently on the lower lip, tongue, and alveolar ridge in either polypoid, exophytic, or endophytic configurations. A male predominance was attributed to a military and veteran bias. Mean age at occurrence was 51 years for men and 67 years for women. Symptoms were infrequently reported. Histomorphologically, fasciculated, myxomatous, and streaming patterns of the spindle cells were observed, with variable mitotic activity, pleomorphism, benign and atypical giant cells, inflammation, vascularity, and infiltration. Follow-up data on forty-five patients revealed that only fourteen were alive and well, whereas twenty-five were dead of their disease. Mean survival time for those dead of the disease was under 2 years. Five-year survival was a significant indicator of cure. No clinical or histomorphologic characteristic other than distant metastasis was found to be a reliable prognostic indicator. Wide surgical excision, alone or with radical neck dissection, was the most successful therapeutic modality. Radiation was ineffective.
ncommon, peculiar, bimorphic tumors, which U have been the subject of considerable controversy within the literature, occur mainly in the upper respiratory and alimentary tracts. Histologically, these tumors, which usually are polypoid in configuration, are composed of surface epithelial changes varying from mild epithelial dysplasiato invasive carcinomain associationwith, and usually dominated by, an abundant dysplastic-appearingspindle-cell component. The controversy concerns the pathogenesisof the spindlecell element and its related clinical, therapeutic, and prognosticbehavior. It has beenconfusingly reportedas carcinomatous,‘-l4 sarcomatous,15-l7 and reactive.18-22 Diagnostic terms, such as spindle cell carcinoma, carcinosarcoma, and pseudosarcoma, reflect this divergence of interpretation. Unfortunately, however, these terms have sometimesbeen applied indiscriminately. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, the Department of the Navy, or the Department of Defense. *Staff, Veterans Administration Dental Training Center, and Department of Oral Pathology, Armed Forces Institute of Pathology. **Vice-Chairman, Deparhnent of Oral Pathology, Armed Forces Institute of Pathology.
Virchow has been credited with the introduction of the term carcinosarcoma to describe neoplasmswith both epithelial and mesenchymal maIignant constituents.l, ’ Certainly, many of the early reports of carcinosarcomawere probably based solely upon the observationof a sarcoma-likeproliferation in combination with carcinomatous elements. In 1938 Saphir and Vass’published an extensive analysis of 153 casesof carcinosarcomareported in the literature, including twenty-two oral, laryngeal, and esophagealtumors. They concluded that most were neither collisions nor combinationsof sarcomasand carcinomasbut were actually carcinomaswith spindling features. More recent reports,15-17however, have reaffirmed the concept of dual malignant head and neck mucosal neoplasms. Proponentsof carcinosarcomahave sited the independent metastasisof the sarcomatousand carcinomatous components and electron microscopic evidence of mesenchymaldifferentiation to support their position. In 1957 Stout and Lattes18and Lane’” independently reportedcasesof polypoid biphasic tumors-Stout and Lattes reporting on tumors of the esophagusand Lane reporting on those of the larynx, fauces, and mouthand proposedthat the sarcoma-liketissues in these lesions were bizarre but nonneoplasticreactive connective tissue responsesto overlying squamouscell carci523
524 Ellis and Corio
Oral Surg. December, 1980
Table I. Vital statistics of fifty-nine cases of spindle cell carcinoma of the oral cavity Sex Male Female
40 19
4s 29-93 yr. 56.6 yr. 51.5 yr. 67.2 yr.
Range Mean Male Female Race White Black Other Not specified Fig. 1. Clinical photographof an exophytic, polypoid lesion of the gingiva and alveolar mucosa with a hemorrhagic appearance.(AFIP Neg. 80-135.)
nomas. They used the termpseudosarcoma . In defining the spindle cell portions as benign, Lanelg noted that there was no transition from carcinomatous to sarcomatoid elements. He observed that the squamous carcinomas were well differentiated in contrast to the pleomorphic spindle cell proliferations and that the sarcomatous elements did not metastasize. His special stains revealed spindle cells enveloped by connective tissue fibers, and he noted that some cases had apparent clinical cures as a result of what he considered inadequate treatment for sarcoma. Subsequent reports20-22 have supported the concept of pseudosarcoma presented by Lane. The majority of oral, laryngeal, and esophageal mucosal spindle cell tumors reported in the literature have favored an epithelial derivation. In 1919 Kettle,23 in one of the earliest reports, advanced the concept that carcinoma cells could assume the morphologic characteristics of mesenchymal cells. Even earlier, Krompecker was reported to have espoused the idea that epithelial cells, under certain conditions, may actually be transformed into mesenchymal cells.23 While this latter idea has not been generally adopted, it has received recent support. l2 Interestingly, foci of osseous and cartilagineous metaplasia have been reported within spindle cell carcinomas. 5*s* 16,24Proponents of a carcinomatous pathogenesis have almost universally cited histologic evidence of transition from epithelial cells to spindle cells. Ultrastructural analysis by electron microscopy has not resolved the pathogenetic dilemma. Goellner and colleagues*l have suggested that the spindle cell component of these bimorphic tumors consists of nonneoplastic histiocytic and fibroblastic cells. Minckler and co-workers’5 and Martin and Kahn” have concluded from electron microscopic studies that the spindle ele-
43 1 3 12
Table II. Anatomic location of fifty-nine cases of spindle cell carcinoma of the oral cavity and follow-up data Anatomic sire
of cases
Died of disease
Alive and well
Lower lip Tongue Alveolar ridge or gingiva Floor of mouth Antrum Retromolar/tonsillar pillar Buccal mucosa Upper lip Hard palate
25 12 II 3 2 2 2 1 1
10 4 3 2 2 2 0 1 1
9 1 4 0 0 0 0 0 0
No.
ments were malignant fibroblasts. On the other hand, Leifer and colleagues9 found, by electron microscopy, that the cells were mesenchymal in appearance but epithelial in origin. Battifora12 reported electron microscopic evidence of the actual transformation of epithelial cells into mesenchymal cells. On the basis of anultrastructural analysis, Shields,8 Someren,r3 Lichtiger,’ and Osamura14 and their associates all supported an epithelial origin for the spindle cell component. It is not our intent to unequivocally prove or disprove any of the histogenetic hypotheses; however, it would seem prudent to attempt to correlate the histomorphologic features with the clinical features and biologic behavior of a series of these bimorphic lesions. A few series of cases from the larynx and esophagus have been reported. ** 5, lo, 11,*l, 25Of these, Hyams’rO study of thirty-nine laryngeal lesions was the most extensive. Brooks26 reported on 110 cases from areas throughout the body but did not elaborate on specific numbers of cases or the biologic behavior of lesions from oral, pharyngeal, or laryngeal sites. Only a small number of oral mucosal lesions have been reported,3B 4, ‘* g, l*, 13, 19, 24, 27-30 and four cases make up the largest series.3’‘, ls In order to give greater definition to these
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of an exophytic,polypoidspindlecell carcinomawith ulceratedsurface. Fig. 2. Low-powerphotomicrograph (Hematoxylinandeosinstain. Magnification,x2. AFIP Neg. 80-522.) Table Ill. Symptoms in twenty-three patients with spindle cell carcinoma of the oral cavity Svmptom Swelling Pain Nonhealing ulcer Dysphagia Hemorrhage Loose teeth
Table IV. Clinical features in patients with spindle cell carcinoma of the oral cavity
No. of patients 7 7 5 2 I 1
biphasic malignant neoplasms, we have reviewed the clinicopathologic characteristicsof fifty-nine “spindle cell carcinomas” of the oral and maxillary sinus mucosa that were submitted for consultation to the Armed Forces Institute of Pathology. MATERIALS AND METHODS
The files of the Armed Forces Institute of Pathology (AFIP) include casematerial submitted by pathologists from military, Veterans Administration, and civilian sources. This sNdy was based on fifty-nine selected casesfrom material submitted to the AFIP for consultation. Requirementsfor inclusion in the study were (1) origin of the lesions in the maxillary sinus or oral mucosa, defined as extending from the vermilion borders of the lips to the tonsillar fauces; (2) adequateclinical information and histologic material available for review; and (3) histologic demonstration of epithelial
NO.
Died oj
of cases disease Size of lesion (cm) Range Mean Duration Range Mean Growth configuration Exophytic Endophytic Not specified History of prior irradiation
0.5-5.0 2.1 2.0
22 22
5 days-4 yr. 9.5 mo.
35 35
10
30 25 4 13
12 10 3 4
changes ranging from prominent dysplasia to frank squamous cell carcinoma in conjunction with a dysplastic spindle cell elementor evidenceof direct transition of epithelial cells to dysplastic spindle cells. Follow-up information was obtained on forty-five of the fifty-nine cases. The standard hematoxylin and eosin stain was employed in all cases, with randomly selected casesinvestigated by one or more of the following special stain techniques: Masson trichrome, phosphotungstic acid-hematoxylin (PTAH), Fontana melanin, reticulum, and periodic acid-Schiff (PAS) with and without prior diastasedigestion.
526 Ellis and Corio
Oral Surg. December, 1980
Flg. 3. Spindle cell carcinoma of the lower lip exhibiting an exclusively endophytic growth configuration. (Hematoxylin and eosin stain. Magnification, X2. AFIP Neg. 77-2538.)
RESULTS Clinical features
Sex, age, race, and location. Over all, a two-to-one male-to-femaleratio was recorded(Table I). However, when only the thirty-eight casesfrom civilian sources were considered, there were twenty-one male and seventeenfemale patients, indicating the male bias expected of casesfrom military and VeteransAdministration hospitals. Ninety-one percent of the patients whose race was noted were Caucasian(Table I). At the time of diagnosis, the patients’ages ranged from 29 to 93 years, with a mean age of 57 years. Interestingly, the mean age for women (67 years) was much higher than that for men (50 years), as shown in Table I. Although lesions occurred in sites throughout the oral cavity (Table II), the lower lip was by far the most frequentsite of occurrence(twenty-five cases).Next in frequencyof occurrencewere the tongue(twelve cases) and the alveolar ridge or gingiva (Fig. 1) (eleven cases). Symptoms. Symptoms were recorded in only twenty-threecases(Table III). Swelling and pain were the two principal symptoms most often documented. Nonhealing ulcer, dysphagia, hemorrhage,and loose teeth were additionalcomplaints.The interval from the onsetof symptomsuntil diagnosis(Table IV), recorded in thirty-five cases,rangedfrom 5 days to 4 yearswith
a mean of 9% months. Particularly noted in several cases,however, was a suddenrapid increasein the size of the tumor. Thirteen patients had a history of prior therapeutic irradiation to the region where a spindle cell tumor subsequentlydeveloped.The time interval from irradiation to diagnosis of spindle cell carcinoma ranged from 1.5 to 10 years, with a mean of 6.9 years. No significant findings as to personalhabits, such as smoking, alcohol intake, or occupation,of the patients could be gainedfrom the available information. Gross pathologic features. The commonly reported polypoid, exophytic growth configuration(Figs. 1 and 2) was manifestedin thirty cases,but a sessile,nodular, or endophytic configuration (Fig. 3) was present in twenty-five cases(Table IV). In four casesthe clinical presentationwas unknown. Tumor size (Table IV), recordedin twenty-two cases,varied from 0.5 to 5.0 cm. in greatestdimension, with a mean of 2.1 cm. These tumors were most often describedas ulceratedbut firm and without central necrosis. Histopathologic
features
More than 93 percentof the lesionsin this serieshad a usually extensivelyulceratedsurfacecoveredwith an eosinophilic fibrinonecrotic material (Fig, 2). While this necrotic surface layer was of variable thickness, foci of necrosis within the central portions of the
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527
Fig. 4. Carcinoma in situ of the oral mucosal surface epithelium (right) adjacent to proliferating spindle cells, which composed the bulk of the lesion. A diffuse, mononuclear, inflammatory cell infiltrate is present. (Hematoxylin and eosin stain. Magnification, ~63. AFIP Neg. 80-524.)
Fig. 5. Moderately dysplastic mucosal surface squamous epithelium (top and left) with apparent transition of the basal cells to spindle cell elements. (Hematoxylin and eosin stain. Magnification, X 100. AFIP Neg. 80-525.)
tumors were rare. This latter finding may be related to the prominent vascularity that the majority of these tumors displayed. The vascular&y was usually most prominent immediately subjacent to the layer of surface necrosis. Despite the vascularity, hemorrhage within the lesions was observed only occasionally.
As a requirement for inclusion in this study, all cases showed either foci of squamous cell carcinoma or evidence of dysplasia of the mucosal epithelium (Fig. 4). This epithelium usually composed a minor portion of the tumor mass and was found mostly within the stalk or periphery of the lesion. Sometimes multiple sections
528 Ellis and Corio
Oral Surg. December, 1980
Fig. 6. Groups of pleomorphic spindle-shapedcells with parallel axes arrangedin an intersecting, fasciculated pattern. (Hematoxylin and eosin stain. Magnification,
X 100. AFIP Neg. 80-526.)
Fig. 7. Spindled and stellate cells with prominent intercellular spaces producing a less cellular, more myxomatous appearancethan the fasciculatedpattern. There is a prominent inflammatory cell infiltrate. (Hematoxylin and eosin stain. Magnification, x 100. AFIP Neg. 80-531.)
were r(squired before it could be demonstrated. In some lesionsi no surface epithelium was present on the sections savailable for study, but foci of poorly to welldiffere ntiated squamous cell carcinoma were found within the spindle cell tumor mass. In those cases which revealed only mild to moderate epithelial dysplasia, there was required evidence of proliferation of
basal cells with transition to spindle cell elements. This transition or “dropping-off” phenomenon was observed in many tumors (Fig. 5). The dysplastic spindle cell components usually constituted the greatest portions of the tumors and presented varied histomorphologic features. Tissue patterns could be categorized as fasciculated, myxcama-
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Fig. 8. Markedly pleomorphic spindle, stellate, and giant cells in a noncohesive,nonoriented,so-calledstreaming pattern. (Hematoxylin and eosin stain. Magnificatip, x 100. AFIP Neg. 80-530.)
Fig. 9. Both benign-appearing,mul&tcleated, foreign body type giant cells (right) and atypical tumor giant cells wlth multiple pleomorphic nuclei (left) were seenwithin the spindle cell componentof thesetumors. (Hematoxylin and eosin stain. Magnification, x403. AFIP Neg. 80-133.)
tous, or streaming. A fasciculated pattern (Fig. 6), the most common of the patterns, was composed of highly cellular groups of elongated bipolar cells in parallel alignment with the fascicles interwoven. The cell nuclei were elliptical and vesicular, and each contained
one or more nucleoli. A variable number of rounded cells with more abundant cytoplasm and round vesicular nuclei were scattered among the elongated cells. The less cellular myxomatous pattern (Fig. 7) showed prominent intercellular spaces, with the cells more
530 Ellis and Corio
Oral Surg. December, 1980
Fig. 10. Osteoidformationin a tumor from the mandibularalveolarridge. (Hematoxylinand eosin stain. Magnification,x 100.AFIP Neg. 80-527.)
pleomorphic and stellate in form than in the fasciculated pattern. The nuclei were more sphericalbut were still vesicularwith conspicuousnucleoli. The streaming pattern (Fig. 8) was depicted by moderately cellular groups of spindle and pleomorphic cells arrangedin randomly orientedcords and sheetswithout notableintercellular edemaspacesor interweavingfascicles. Although one tissue pattern was often dominant within a tumor, most lesions presenteda combination or spectrumof histologic patterns.In general, cellular and nuclear pleomorphismwere more prevalentin the myxomatous and streaming patterns, but all patterns exhibited wide variation. Likewise, the number of mitotic figures, a significant feature, was quite variable, even from focus to focus within an individual tumor. Mitoses ranged from one per ten high-power fields to five per high-power field. Becauseof the cellular density, tumors with a fasciculatedpattern tended to have a larger number of mitoses per high-power field but not necessarilymore per numberof cells observed. Multinucleated giant cells were a common finding within the spindle cell component (Fig. 8). Both benign-appearinggiant cells of the foreign-body type and bizarre, pleomorphicatypical giant cells were seen (Fig. 9). In addition, acute and chronic inflammatory cell infiltrates, mild to moderatein intensity, were frequently dispersedthroughoutthe spindle cell elements (Figs. 4 and 7). Special stains confirmed that the supportingstroma of most tumors was scant and varied from fibrillar to
densely collagenous.In four cases, all involving the mandibularalveolarridge or gingiva, osteoidformation within the dysplastic spindle cell componentwas observed (Fig. 10). Neither intracytoplasmiccross striations nor melanin pigment could be demonstratedby special staining techniques. Infiltration of subjacentstructures, such as skeletal muscle, bone, salivary glands, and nerves, by spindle cells was exhibited in thirty-two cases.While involvement of thesedeep structureswas more frequently observed in tumors with an endophytic configuration, it was often seenin exophytic lesions as well. Tissue from metastatic foci was available for histologic study in six cases; the tissue was taken from four cervical lymph nodesand two pulmonarylesions. In four casesthe metastaseswere composedof spindle cell elementsonly, while in two casesthe metastases contained squamouscell carcinomatousand spindle cell “sarcomatous”elementstogether(Fig. 11). The initial interpretationby thirty of the contributing pathologists was carcinoma. Twelve others classified their lesionsas sarcoma,most commonly fibrosarcoma. Undifferentiatedmalignant neoplasmwas the submitted diagnosisin two cases, and benign fibrous lesion was the diagnosisin five cases.No opinion was expressed in ten cases. Therapy and follow-up data
A generalcharacterizationof methodsof therapyand their results is given in Table V. Follow-up data were
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531
Fig. 11. A cervical lymph node which contains metastaticfoci of both ‘‘carcinomatous”(right) and “sarcomatous” (left) elements. (Hematoxylin and eosin stain. Magnification, ~63. APlP Neg. 80-134.)
obtained in forty-five of the fifty-nine cases (Table VI). Fifty-five percent of these patients were dead of their disease, and only 31 percent were alive without evidence of residual or recurrent tumor. Three patients died of other causes without evidence of having the study disease, and two patients had tumors but died of unrelated causes. One patient was alive with the disease. The mean follow-up interval (Table VII) for those patients still alive and well was less than 5 years. The mean survival time of those patients dead of the disease was 1.9 years. Documentation of recurrent tumor was noted in twelve cases, and metastasis was noted in sixteen. The cervical lymph nodes were the most frequent site of metastasis (eleven cases). Four of seven patients with cervical lymph node metastasis alone and all nine patients with distant metastases were known to have died of their disease (Table VIII). The death rate was not influenced by tumor size, gross configuration, or a prior history of irradiation (Table IV). While the prognosis was not good for spindle cell carcinomas arising in any oral location, those whose tumors occurred on the lower lip had the best survival rate (Table II). Although each lesion in the series was classified as to predominant tissue pattern and subjectively quantified as to amount of pleomorphism, mitotic activity, number of giant cells, extent of inflammatory infiltrates, and amount of hemorrhage and necrosis, no histomor-
Table V. Therapy in fifty-nine cases of
spindle cell carcinoma of the oral cavity and follow-up data NO. Therapy Surgery Surgery with RND*
Radiation Surgeryand radiation Surgerywith RND* and radiation Chemotherapy Not specified
of cases
Died of disease
Alive and well
5
1 2
5
41
12 3
7 It
3 0 3 1
I
I
0
6
3
1
21
6
* RND = Radicalneckdissection. t One additionalpatienthad the study diseasebut died of other causes. phologic characteristics were found to be more prominent or to occur more frequently in tumors from patients who died of their disease than in tumors from patients who were alive and well. DISCUSSION
Whether these biphasic neoplasms of the oral cavity represent a squamous cell carcinoma associated with an atypical, benign, reactive connective tissue process (pseudosarcoma), a combination or collision growth of a carcinoma and a sarcoma (carcinosarcoma), or a squamous cell carcinoma with a peculiar spindle ccl
532 Ellis and Corio
Oral Surg. December, 1980
Table VI. Follow-up data on forty-five patientswith
spindle cell carcinomaof the oral cavity Status
No. of patients
Alive and well Alive with disease Dead of disease Dead of other causes Dead of other causeswith disease
14 1 25 3 2
TaMe VII. Follow-up interval for forty-five patients with spindle cell carcinomaof the oral cavity
All patients Patients alive and well Patientsdeadof disease
Range
Mean
1 mo.-I 1 yr. 8mo.-11 yr. 1 mo.-6 yr.
3 yr. 4.5 yr. 1.9yr.
Table VIII. Follow-up information on casesof spindle cell carcinomaof the oral cavity: Recurrencesand metastases
Recurrences Metastases* Cervical lymph nodes Lung Heart Skin Bone
No. of cases
Dead of disease
12 16 11 6 1 1 1
7 13 8 6 1 1 1
*Four patientshad both cervical lymph node and distant metastases.
anaplasia(spindlecell carcinoma)is a questionof more than academicinterest. Prognosisand treatmentdepend upon the conceptof pathogenesisadopted. Evidenceof local and distant metastasisof the spindle cell element,documentedin six casesin this series, and an over-all deathrate of forty-two percent(55 percent of the patientswith follow-up) would seemto preclude an interpretation of a benign reactive process. Conversely, the independentmetastasisof “sarcomatous” elementsand a high deathrate lend supportto the concept of carcinosarcoma.However, certain features argue againstcarcinosarcoma.First, areasof transition of basal squamousepithelial cells to spindle cell forms were common histologic observationsin thesetumors. Battifora12haspresentedelectronmicroscopicevidence of modulation of cellular characteristicsfrom epithelial, to epithelial and mesenchymaltogether,to mesenchymal. Second, lymphatic spreadwas the most frequent metastatic pathway, the predominant route of carcinomas.Sarcomasmore often embolize via blood
vessels.31Third, the averageage at occurrencecorrelated with that for squamouscell carcinomaof the oral mucosa.32Finally, although these lesions are uncommon, the simultaneousoccurrence of epithelial and mesenchymalmalignant neoplasmsat the same site would seem to be distinctly rare. Electron microscopicstudieshave proved contradictory, with various reports interpreting the spindle elements as benign mesenchymal, malignant mesenchymal, and malignantepithelial.7-g,12-15* I’, 21From the largest seriesstudied by electron microscopy (thirteen cases), Lichtiger and colleagues7concludedthat the spindle cell component was carcinomatous in nature. Although the evidence is circumstantial, we subscribe to the conceptthat thesebimorphic tumors of the oral cavity representa variant of squamouscell carcinoma, and we prefer the term spindle cell carcinoma. Analysis of this series of fifty-nine casesindicated that thesetumorsoccurredmost frequentlyon the lower lip, tongue, and alveolar ridge of Caucasianmen of middle age and older. The male preferencewas nearly eliminated when only casesfrom civilian sourceswere evaluated.Previousreports have indicateda male predominance.5,‘, lo* l1 Unexplainedwas the significantly older mean age at occurrencein women. On the lip most tumors had a endophytic growth configuration, while in other locations most lesions were exophytic. Tumors in the larynx and esophagushave been reported to cause hoarseness,dysphagia, and obstruction,5. loa11,33but few of the casesof oral lesionsin this seriesrecordedany symptoms.Pain and swelling were the symptomsmost often noted. Of the forty-five patients on whom follow-up data were obtained, only fourteen were alive and without evidenceof disease,and only six of thosefourteenhad been followed for 5 years or longer. When the three patientswho died of other causeswere not considered, the survival rate was 36 percentwith follow-up periods ranging from 8 months to 11 years. That figure was lower than previously reported for spindle cell carcinorna’O*l1 but was consistentwith that for squamous cell carcinomaof the oral mucosa32 and that reportedby Appelmanand Oberman5for spindle cell carcinomaof the larynx. The meansurvival time following treatment for the twenty-five patients who died of their disease was less than 2 years; therefore, a 5-year survival would seemto be significantly indicative of cure. Certain clinical features of spindle cell carcinoma have previously been implicated as having prognostic significance.A polypoid, exophyticgrossconfiguration has been thought to have a better prognosisthan a sessile, endophytic configuration.4-g*13*34In this series, however, forty percent of the patients with exophytic
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tumors and 40 percentof the patients with endophytic lesions succumbedto their disease.Randall and associates,” who reportednine casesfrom the larynx, and Brooks,2”who reviewed 110 casesfrom many locations, stated that the size of the tumor was the only reliable indicator of prognosis.In the current study the mean size of tumors in patients who died of their disease was actually fractionally smaller than the mean size of all lesions. It has also beenreportedthat therapeutic irradiation to the site of subsequentappearance of a spindlecell carcinomawas a contributingetiologic facto+ i. 9, XJ*2i and that the prognosiswas worse in such cases.:]A history of prior radiation was documentedin thirteen casesin this review of oral spindle cell carcinomas.A thirty percent death rate for these patientssuggestedthat a history of radiationwas not an important prognosticfactor. Radiation may have been an etiologic factor. As would be expected, metastasissignaled a very poor prognosis.In this study 81 percentof the patients with recordedmetastasisdied of their disease.All nine patientswith known metastasesof distant organsdied. In an attemptto correlatethe histopathologicfeatures of spindle cell carcinomawith prognosis,the features of lesionsfrom patientswho died of their diseasewere comparedto the over-all incidence or prominenceof such features.The predominanttissuepattern (fasciculated. myxomatous, or streaming), degree of pleomorphism, numberof m itotic figures, number of giant cells, amount of inflammatory cell infiltrate, presence of hemorrhageand necrosis,and extent of invasioninto subjacenttlssue structureswere evaluatedand found to be neither significantly more nor less prominent in tumors that resultedin the deathof the patient. Formation of osteoid-appearingmaterial within the spindle cell componentwas found in four cases, all occurring on the alveolar ridge. This finding lead to speculationthat theselesionsmay have beenosteosarcomas arising from the periosteumor alveolar bone. However, these tumors met all the criteria for spindle cell carcinoma as previously defined. Osteoid and chondroid material have been reported in spindle cell carcinomasof the larynx5 and in lymph node metastasesfrom spindlecell carcinomasof the tongueg3 24and larynx. I6 Although the prognosisfor spindlecell carcinomaof the oral cavity was not good, surgical intervention, with or without radical neck dissection, resulted in a better survival rate than radiation alone or a combination of radiation and surgery. In this seriesfollow-up datarevealedthat nine of eighteenpatientstreatedwith surgery alonewere alive and well. However, only four of eighteen patients treated with radiation, alone or with surgery, were alive and without disease.These
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results are in agreementwith Hyams”O finding, in a study of thirty-nine spindle cell carcinomas of the larynx, that radiation therapy was ineffective. Chemotherapy was employed in only one case in our series, and the patientdied of the disease.The value of radical neck dissectioncould not be determined.
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