Epithelial Epidermoid Tumors : Part II
Squamous Cell Carcinoma Variants
The Association of Human Papilloma Virus with Benign and Malignant Sinonasal Neoplasms
Human papilloma viruses (HPVs) are prevalent pathogens, and their epidemiology has been mostly studied in the uterine cervix and the vagina, beginning as long ago as the 1950s. The carcinogenicity of HPV infection in this area is well established and recent details of this large area of research are covered in detail in the IARC monograph (volume 90) published in 2007.1 Even this excellent monograph on human papilloma viruses shows that there are considerable areas where we do not have a full understanding of the major steps necessary for carcinogenesis subsequent to HPV infection, persistence of that infection, progression to precancerous lesions, and eventually invasion. We now understand that provided invasion has not taken place, this process is reversible by clearance of HPV infection and regression of the precancerous change. HPV infection can be separated into low viral load infections that do not produce any microscopically evident abnormalities, and higher viral load infections that do. Most of our knowledge refers to HPV16, which is the type most frequently found in tumors in the general population.
The role of human papilloma viruses in head and neck lesions has been far less extensively studied, but even within the research that has been done there are widely varying reports with regard to the incidence of HPV involvement in both benign and malignant lesions. The literature can be contradictory and confusing. It is widely accepted that persistence of HPV infection is essential for the development of cervical precancerous lesions and cancer, but from the extensive studies in this area we know that most HPV infections are transient and become undetectable within 1 to 2 years, even by sensitive PCR assays. Consequently, these anogenital HPV infections tend to resolve spontaneously, as indeed do warts anywhere else on the body. We can assume, therefore, that they are cleared completely by the cell-mediated immune system or are self-limited or are suppressed into long-term latency. These issues remain a significant unresolved question when considering the natural history of HPV and which infections are cleared. It may be that small foci of cells can maintain infection with low DNA copy numbers, even when no HPV DNA is detectable by the variety of molecular tests. There are still many answers required to these questions. Persistence of HPV infection appears to be uncommon compared with clearance and there is certainly no consensus on the length of time of perceived persistence that goes on to produce precancerous or cancerous lesions. The supposition is that the longer duration of infection with high-risk types of HPV may have obvious implications for the production of cancer, but as yet there is no agreement on a uniform definition of HPV persistence.
There are now over 100 types of human papilloma viruses described and infection is so common worldwide that it is far from straightforward to assess whether the presence of HPV contributes to tumor formation. Advances in the understanding of the natural history of HPV are still required and, while intensive efforts have been made to standardize accurate and reliable measurements of HPV DNA, most of the variable results from the late 1980s and 1990s in the study of cervical cancer were caused by unsuspected misclassification of HPV status in the original large-scale molecular epidemiological studies. In the area of the head and neck, which has been studied to a far lesser degree, it is therefore not surprising that results using different methods on smaller numbers of specimens have produced varying conclusions. In the future, with further additional improvements in cytology and serology, it will be important to optimize methods to improve our interpretation of the patterns of viral involvement, viral clearance, persistence, and progression of disease.
HPV Prevalence in Squamous Cell Carcinoma of the Head and Neck
At the time of writing, the previous decade of research related to HPV prevalence in association with squamous carcinoma has shown between 20% and 30% correlation for oropharyngeal, hypopharyngeal, and laryngeal squamous carcinomas, with a correlation up to 50% with squamous cell carcinoma of Waldeyer’s tissue within the tonsil ring. The evidence is particularly compelling for oropharyngeal carcinomas, particularly those of the tonsil.2–5
Clear identification of this subset of tumors has been of considerable clinical interest because although it initially appeared that these lesions presented more aggressive behavior, with the HPV-positive patients usually presenting with a higher lymph node status (which normally is a strong predictor for decreased survival times), the converse was found to be true and HPV positivity was related to increased times to recurrence and improved overall survival times following treatment.
In contrast to the oropharynx, the evidence with regard to the larynx or sinonasal cavities is far less conclusive and the IARC 2007 monograph stated that the evidence for the larynx was limited and that there is inadequate evidence in the sinonasal area.1 Of the previous reports suggesting possible implication of HPV in the development of carcinomas in the sinonasal region, those of Hoffman et al, Syrojanen et al, El-Mofty and Lu, and Alos et al are of note.6–9 In the most recent of these studies from Barcelona,9 60 squamous cell carcinomas of the sino-nasal tract seen between 1981 and 2006 were reviewed retrospectively. HPV infection was determined and typed by amplification of HPV DNA by PCR. P16 expression was determined by immunohistochemistry. HPV DNA was detected in tumor tissue of 12 of 60 patients (20%). HPV16 was identified in 11 tumors.
Immunohistochemistry for P16 stained all HPV-positive and no HPV-negative tumors. In 12 cases, the carcinoma was said to develop on a sinonasal inverted papilloma that coexisted in 11 cases and had previously been excised in one case. This is certainly a very high incidence of this association with squamous carcinoma and leads to some concern about the validity of the data. Only one of the carcinomas arising on a sinonasal inverted papilloma tested positive for HPV16.
On the basis of Kaplan-Meier estimates, HPV-positive tumors statistically had a significantly better survival than HPV-negative tumors, being 62% at 5 years in contrast to 20%. On multivariant analysis, HPV status retained statistical significance. This publication appears to be the first evidence of better survival of HPV-positive tumors in sinonasal squamous cell carcinomas, but the conclusions drawn from this relatively small series of patients remain to be confirmed by further studies.
Verrucous Carcinoma
Definition
(ICD-O code 8051/3)
Verrucous carcinoma is a rare, low-grade variant of squamous cell carcinoma and characteristically has a warty or papillary appearance, producing an exophytic mass that is composed of keratinizing, well-differentiated epithelium.
Etiology
Friedell and Rosenthal10 were the first to describe 8 cases in the oral cavity with a papillary verrucoid appearance. However, it was Ackerman11 who coined the term “verrucous carcinoma” and recognized its clinical significance and good prognosis when treated by surgery.
Hanna and Ali12 implicated use of snuff, use of chewing tobacco, and poor oral hygiene as etiological factors in verrucous carcinoma. A more recent report by Karthikeya et al13 from India also associated intranasal snuff and smoking with an extensive intranasal verrucous carcinoma.
Human papilloma virus has been identified in many benign and malignant lesions of the upper aerodigestive tract, and colleagues at the Mayo Clinic14 in 1999 reported a retrospective group of 13 patients with intranasal verrucous carcinomas seen between 1960 and 1996. Ten presented with nasal obstruction and the maxillary sinus was the extranasal site most often involved. Five patients had verrucous carcinoma developing in inverted papilloma and one a squamous carcinoma with a verrucous component. In 7 patients (10 specimens), DNA was successfully amplified for PCR testing and no HPV DNA was detected. No role for HPV in the etiology of these tumors was found.
Synonyms
Ackerman tumor.
Incidence
Verrucous carcinoma of the nose and sinus is a very rare tumor and overall the maxillary sinus appears to be the most common site, followed by the nasal fossa. We have only treated two cases, both in elderly women (75 and 90 years old, respectively). Nasopharyngeal lesions encroaching into the nasal cavities have been reported.15
Diagnostic Features
Clinical
By far the majority of patients in the literature are men and most are smokers or users of snuff as noted above. The most common presenting symptom is nasal obstruction in ~75% of the cases, in addition to the majority being aware of an intranasal lesion. Approximately one-third present with pain that is more common in those with disease developing in the maxilla. Unilateral mucopurulent rhinorrhea may be long-standing and swelling of the cheek, loosening of the teeth, the inability to fit dentures, trismus, and a visible lesion presenting in the oral cavity are all found in those patients with maxillary involvement.
Verrucous carcinoma generally presents in the 50- to 80-year-old age group and the symptoms may be longstanding, with reports of symptoms for up to 2 years prior to presentation.
Intranasal examination usually reveals an extensive, expansile exophytic lesion, often visible in the nostrils, with the lateral wall of the nose being the commonest site in those lesions where the site of origin can be discerned.14 Approximately half the patients with intranasal lesions will have evidence of further spread into the maxilla and ethmoid sinuses. A careful intraoral examination is necessary to evaluate teeth, the possibility of a sinus tract, simple edema, or a definitive mass. It may be difficult to know whether some of the more extensive lesions arose in the oral cavity or intranasally.
The literature contains examples of these lesions appearing in association with both inverted papilloma and benign nasal polyps and, although the lesions are extremely rare, this once again demonstrates the need for accurate histology on all nasal polypoid masses and adequate examination of the nasal cavity at the time of removal of any benign nasal polyposis.
Imaging
Depending on the extent of the lesion, CT, MRI scans, and orthopantomograms are all useful. Indeed, simple sinus plain radiographs may show diffuse radiopacity and bone destruction, particularly for those lesions within the maxillary sinus. Coronal CT sections are particularly useful for showing destruction within areas such as the floor of the maxillary antrum or nasal cavity as well as spread into the ethmoid sinuses. MRI may be indicated in addition if the lesions are large enough to encroach on the orbit or skull base.
Histological Features and Differential Diagnosis
Verrucous carcinoma is a lesion that continues to be difficult to diagnose on occasions. Diagnosis from a small or superficial biopsy may be impossible, with only hyperkeratosis, acanthosis, and apparently benign papillomatosis in the material. Cooper et al16 showed that mean cell and nuclear areas were significantly higher in verrucous carcinoma than in squamous papillomas, giving a mean cell area above 300 µm2 as a useful dividing point to establish malignancy. Foci of typical squamous carcinoma may occur within a tumor, which otherwise looks exclusively verrucous. This subgroup has a higher recurrence rate. The surgeon must provide the pathologist with not only the details of the history, which is often prolonged, but an ample representative sample or excisional biopsy to aid in an accurate diagnosis.
The differential diagnosis of verrucous carcinoma includes exophytic squamous cell carcinoma, papillary squamous cell carcinoma, and keratinizing inverted papilloma.
Natural History
Verrucous carcinoma is a slow but locally invasive neoplasm that can cause extensive local destruction if left untreated. True verrucous carcinoma does not metastasize, but, when it is associated with squamous carcinoma, the potential for lymph node metastasis is present and clearly these patients should be managed as if they had squamous cell carcinoma. These rare cases of verrucous carcinoma within the nose and sinuses have an excellent prognosis but they must be fully excised as recurrence with inadequate treatment remains a problem.
Treatment and Outcome
Patients with verrucous carcinoma may be treated by a wide variety of excisional surgery and, not surprisingly, depending on the size and site of the presenting lesion, surgical options have included endoscopic excision, lateral rhinotomy, total rhinectomy, maxillectomy, with and without orbital exenteration, and craniofacial resection. Those with extensive disease in particular, may require further surgery for recurrence but in the Mayo Clinic series14 with follow-up ranging from 2 months to 32 years (mean 6.5 years), none of the 13 patients with nose and paranasal sinus verrucous carcinoma had metastases and none died because of the tumor. While the literature still has a tendency to quote the fear of anaplastic transformation of verrucous carcinoma after radiotherapy, critical review of these reports has shown that many are unrecognized, hybrid verrucous carcinoma associated with squamous carcinoma. They have been inappropriately labeled as verrucous carcinoma.14,17,18 Radiotherapy can be an effective treatment for this disease and indeed was the treatment given to our two patients with good results, both surviving longer than 5 years.
Papillary Squamous Cell Carcinoma
Definition
(ICD-O code 8052/3)
Papillary squamous cell carcinoma (PSCC) is a distinct variant of squamous cell carcinoma that has an exophytic, papillary configuration with thin fingers of malignant epithelium overlying a central fibrovascular core. The surface epithelium may resemble that seen in intraepithelial neoplasia or high-grade dysplasia with minimal keratosis.
Etiology
The majority of papillary squamous cell carcinomas of the head and neck have been reported in the larynx and hypopharynx, and both smoking and alcohol have been implicated as factors.19,20 However, the rarity of lesions presenting in the nose and sinuses does not allow extrapolation of this data as an etiological factor in the sinonasal tumors.
As with other variants of squamous carcinoma, human papilloma virus, notably HPV16, has been suggested as an etiological factor, but the prevalence of HPV in a wide variety of studies of head and neck tumors commencing in the 1980s has reported a prevalence of HPV varying from 0 to 48% in papillary squamous carcinoma.21 Comparison of HPV DNA detection rates between the published studies is confounded by the different molecular biological techniques used, different sites and patient details, and the often small sample sizes. In general a reciprocal relationship has been found between p53 and HPV prevalence. The role of HPV in the etiology of papillary squamous carcinoma therefore still requires further investigation. Indeed, papillary squamous cell carcinoma of the sinonasal region is a poorly understood variety of squamous carcinoma in this region and, because of its very low incidence, it may be confused with verrucous carcinoma, exophytic conventional squamous cell carcinoma, or inverted papilloma.
Incidence and Site
Papillary squamous cell carcinoma may be derived from preexisting papillary mucosal hyperplasia or squamous cell papilloma, although in the report of Suarez et al21 of 38 cases from all sites in the head and neck, only 2 papillary squamous cell carcinomas exhibited histological evidence of a preexisting papilloma. However, 34% of the patients had a history of previous papillomas at the site of the subsequent papillary carcinoma. Unfortunately, the paper does not contain precise clinical details of the 11 sinonasal cases and 5 nasopharyngeal cases (out of 38), nor of the length of time over which these cases were collected.
Diagnostic Features
Clinical
Unilateral nasal obstruction and epistaxis are the commonest presenting symptoms and, on examination, the lesions within the nasal cavity are usually soft, friable, pedunculated, exophytic papillary masses. The base of the pedicle is often small, but broad-based lesions have been reported. Less than 10% of patients with papillary squamous cell carcinoma of the entire head and neck area present with cervical metastases and pulmonary metastases are extremely rare.
Histological Features and Differential Diagnosis
The multiple papillary projections of these lesions have a central fibrovascular core covered by the malignant epithelium, which is usually composed of nonkeratinized, immature basaloid cells or more pleomorphic cells. Multiple papillary squamous carcinoma has been reported along with evidence of papillary precursor lesions. Of considerable importance is the finding of stromal invasion, which may consist of single or multiple nests of tumor cells with a chronic lymphoplasma cellular infiltrate in the lamina propria adjacent to the carcinoma, but minimal elsewhere within the papillary cores. These findings are in contrast to squamous papilloma and verrucous carcinoma, which, although having similar architecture, do not have the same findings of atypia of the epithelium. The most notable difficulty reported by colleagues in pathology seems to be differentiating between exophytic SCC and papillary SCC, but in general the papillary stalks of PSCC are much better defined than in exophytic SCC.22
Treatment and Prognosis
While the available literature describes the prognosis of these lesions in the larynx as favorable, the sinonasal papillary carcinomas were found by Suarez et al21 to be the most lethal. Detail is missing from their publication, but 11 of 25 patients (44%) with a median long-term follow-up of 3 years died of disease. Recurrence and sinonasal tumor site were the only factors related to outcome. All patients had been treated with surgery and radiotherapy, but no details were available and it is not possible to draw definite conclusions on treatment from a paper whose aim was to define the clinicopathological characteristics of papillary squamous cell carcinoma.
Basaloid Squamous Cell Carcinoma
Definition
(ICD-O code 8083/3)
Basaloid squamous cell carcinoma is a generally aggressive high-grade variant of squamous cell carcinoma, having both basaloid and squamous cells, usually closely packed and in a solid pattern.
Etiology
While tobacco use and alcohol use have been strongly implicated in basaloid squamous cell carcinoma (BSCC) in pharyngeal and laryngeal sites, it is difficult to be certain of their relevance for the rare cases reported in the sino-nasal complex.23–25 It remains controversial whether Epstein-Barr virus (EBV) or human papilloma virus (HPV) are contributory factors in BSCC. Wan et al reported three cases of nasopharyngeal BSCC in which they detected EBV.26
Synonym
The terms basaloid carcinoma and adenoid cysticlike carcinoma have both been used in the past.
Incidence and Site
BSCC was initially described by Wain et al27 in 1986 in cases involving the tongue, hypopharynx, and larynx. Subsequent reports have confirmed that the head and neck is the most frequently involved area but with larynx, pharynx, and oral cavity sites predominating. Nasopharynx and sinonasal tract cases are extremely rare and we have only one case in a series of 320 squamous carcinomas and variants, a 75-year-old man. In 20 head and neck cases reported in the year 2000 from the combined departments of the University of Michigan, Ann Arbor, and the Memorial Sloane Kettering Cancer Center, New York, from between 1975 and 1997,25 only 2 cases occurred in the nose and one in the nasopharynx (the latter in a nonsmoker).
Diagnostic Features
Clinical
Basal cell carcinoma presents predominantly in men between 60 and 80 years of age.
In contrast to verrucous and papillary carcinoma, BSCCs within the nasal cavity usually appear as a solid mass, often with considerable induration and ulceration with easily induced bleeding on examination. The clinical history of nasal obstruction and epistaxis is more often accompanied by pain and of significantly shorter duration than other forms of squamous carcinoma. Again, in contrast to the other variants, they appear to present with advanced T stage in all reports; metastases to the regional lymph nodes are more common and distant metastases involving the lungs, bones, skin, and brain have been reported to occur in as many as 50% of the patients. As a consequence of the aggressive nature of these lesions, nasal and cheek deformities, paresthesia, proptosis and diplopia are more likely to be clinical features of this rare form of squamous carcinoma.
Imaging
CT and MRI are often required to delineate the full extent of the lesion as there is frequently significant bone invasion and extension to neighboring structures such as the orbit, pterygopalatine fissure, infratemporal space, and anterior cranial fossa (Fig. 6.30). The lesions may extend bilaterally prior to diagnosis with involvement of the opposite ethmoid complex and substantial erosion of the nasal septum.
Histological Features and Differential Diagnosis
As a consequence of its extreme rarity in the sinonasal tract,27 BSCC is rarely suspected clinically and has to be differentiated from other aggressive sinonasal malignancies. Weineke et al28 identified only 14 cases from the sinonasal tract in the files of the Otolaryngologic Head and Neck Pathology Tumor Registry at the Armed Forces Institute of Pathology over a 21-year period between 1975 and 1996.
Difficulties arise as a consequence of the fact that basaloid squamous cell carcinoma is frequently associated with a more standard well- or moderately differentiated squamous cell carcinoma component, which may in itself be associated with in situ carcinoma or frank invasive keratinizing squamous cell carcinoma. There may also be areas of squamous differentiation within the basaloid tumor islands, with an abrupt change from basaloid to squamous cells. The basaloid cells are frequently in rounded nests and are highly atypical with hypochromatic nuclei and considerable mitotic activity. There are often areas of comedo-type necrosis and a pseudoglandular arrangement that can cause confusion with adenoid cystic carcinoma.
Metastases may be composed of basaloid carcinoma, keratinizing squamous cell carcinoma, or both.28,29
The differential diagnosis includes adenoid cystic carcinoma, adenosquamous carcinoma, and neuroendocrine carcinoma. While modern immunohistochemistry and electron microscopy can help considerably here, it is important to remember that adenoid cystic carcinoma only very rarely spreads to cervical lymph nodes and only in the solid variant with advanced disease. Palpable metastatic nodes in association with BSCC are quite common, even from sinonasal lesions. Immunohistochemistry may require a variety of cytokeratin antibodies, but the antibody 34 β E12 directed against the high molecular weight cytokeratins is said to be the most sensitive for the detection of basaloid cells. The presence of dotlike vimentin expression in BSCC can also be helpful, and the absence of any myoepithelial cells helps to distinguish between BSCC and adenoid cystic carcinoma.23
In a substantial report published in 2004, the multidisciplinary team from the MD Anderson Cancer Center reported a study that performed molecular analysis on 92 squamous cell carcinoma variants from the head and neck.30 These comprised 44 primary, untreated, conventional squamous cell carcinomas between 1985 and 2001, and 48 variant carcinomas (18 verrucous, 6 papillary, 7 basaloid, and 17 sarcomatoid). These were assessed using microsatellite markers and loss of heterozygosity (LOH). Overall, a higher than average incidence of LOH was found at most (15/21) of the markers tested in the basaloid squamous cell carcinomas. These differences were significant and distinguished between the other variant carcinomas, particularly at markers D9 S157 and D11 S4167. This study showed significant association between certain clinicopathological factors and LOH with significant statistical associations being found between the incidence of LOH, age, size, site, stage, and patient survival. This study is an example of markers that might prove to be useful in the future and might assist with the early detection and diagnosis in individuals in the future.
Treatment and Natural History
Of the 14 sinonasal cases of Wieneke et al,28 13 received primary surgery (no details) and 5 adjuvant radiotherapy. Chemotherapy was given to 2 patients; 7 had recurrence within 2 years of diagnosis, with 4 having distant metastases to bone and lung that are regional lymph node metastases. In 2 patients dura and brain were directly invaded and 10 (71%) either died of disease7 or were alive with disease3 at last follow-up. The average and median times to death were 33 months and 12 months.
As a consequence of the features outlined above, basaloid squamous cell carcinoma in sinonasal sites follows the pattern seen elsewhere in the head and neck and has a poor prognosis. While precise statistics from this rare variant are difficult to gain because of the small numbers involved, some authors feel that it appears to be more aggressive than conventional squamous cell carcinoma when matched stage for stage,27,28,31 but others feel that stage for stage BSCC is similar to conventional squamous carcinoma.23,32 It certainly appears to be the case that modern multimodality therapy must be tried and assessed in these cases. Our patient received radiotherapy following surgical excision and has survived 3 years so far.
Spindle Cell Carcinoma
Definition
(ICD-O code 9074/3)
Spindle cell carcinoma (SPCC) is a tumor that is composed of elements of squamous cell carcinoma, either invasive or in situ, and an additional, usually larger, component of malignant spindle cells that are of epithelial origin but often have a mesenchymal appearance, which has given rise to considerable confusion and misdiagnosis in the past.
Synonyms
These have been multiple and include pseudosarcoma, sarcomatoid carcinoma, metaplastic carcinoma, carcinosarcoma, biphasic tumor, and collision tumor.
Etiology
This rare variant of squamous cell carcinoma has been most commonly described in the glottic area of the larynx and less frequently in the hypopharynx. It is very rare in the sinonasal complex. The laryngopharyngeal tumors have been linked to cigarette smoking and alcohol consumption and radiation, but there is insufficient evidence to link these factors with the production of SCC in the sinonasal area.33,34
Incidence
Of the rare variant tumors of squamous cell carcinoma in the sinonasal tract, spindle cell carcinoma is the commonest variant reported from the largest centers. Of the 48 variant tumors studied in the MD Anderson series reported in 2004, 18 were verrucous, 6 were papillary, 7 were basaloid, and 17 were spindle cell carcinomas (sarcomatoid). These variants were seen over a period of 16 years from 1985 to 2001.35 In our series, there were 9 patients out of a total of 320 squamous cell carcinomas and variants. They were predominantly male (8:1), with ages ranging from 39 to 64 years (mean 54.3 years).
Site
These lesions are rare within the sinonasal tract and most commonly present within the nasal cavity. However, in 6 patients the ethmoids and skull base were affected and in the other 3 the maxilla was the primary site of origin.
Diagnostic Features
Clinical Features and Imaging
These tumors most commonly present with unilateral nasal obstruction associated with rhinorrhea and minor epistaxis; on examination they are frequently polypoidal but may have significant ulceration of the surface and pronounced infiltration at the base. There are no specific features on imaging, but with the larger lesions there will be extensive bone erosion and invasion into the adjacent sinuses.
Histological Features and Differential Diagnosis
The most commonly used synonym for these tumors in the past has been “sarcomatoid,” and when the spindle cell pattern dominates the histopathological picture SPCC can be mistaken for a true sarcoma. Foci of osteosarcomatous, chondrosarcomatous, or rhabdosarcomatous differentiation may be present, but the most common resemblance of these tumors is to fibrosarcoma or malignant fibrous histiocytoma. While the spindle cell pattern usually forms the bulk of the tumor, the squamous component is often seen either as in situ carcinoma or as invasive SCC. Ulceration makes the evaluation of carcinoma in situ difficult and multiple sections may be required to demonstrate the infiltration of the squamous cell component. Further difficulties may be encountered with biopsies of metastases, which may only contain squamous cell carcinoma, a mixture of spindle cell and squamous cell, or rarely only the spindle cell component.34
When the squamous cell component is not apparent in a spindle cell lesion, it is important to investigate for evidence of epithelial differentiation and the tumor cells can express both epithelial and mesenchymal markers. The most useful epithelial markers are currently AE1, AE3, CK1, and CK18, and epithelial membrane antigen. Cytokeratin expression can be demonstrated in spindle cells in up to 90% of cases. Occasionally, spindle cell carcinomas can be confused with other spindle cell proliferations such as inflammatory myofibroblastic sarcoma and myoepithelial carcinoma.35 The recent molecular evidence has shown a significantly higher frequency of LOH at marker D4 S2632 for spindle cell carcinoma compared with the other variant forms and the overall molecular evidence would suggest that SPCC is a monoclonal epithelial neoplasm with divergent mesenchymal differentiation.36,37 However, continuing debate on this subject is fierce and it is at the very center of our traditional histological classification of tumors.
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