Histopathological Variants of Oral Squamous Cell Carcinoma Operated at a Cancer Institute in North India

Abstract

Conventional oral squamous cell carcinoma (OSCC) is one of the most common cancers of the head and neck region. However, histopathological variants of conventional oral squamous cell carcinoma also exist, which range from highly aggressive to those with good prognosis. Here, we present a case series of different histopathological variants of conventional OSCC treated at our institute. A retrospective chart review was performed to search for squamous cell carcinoma of the oral cavity, which were operated at Rohilkhand Cancer Institute, Bareilly, Uttar Pradesh, India, from August 2018 till December 2023. Electronic database was searched for this purpose, and the histopathological variants of oral squamous cell carcinoma that underwent curative intent surgery including neck dissection, with or without adjuvant treatment were included in the form of case series. Clinico-pathological details of the histopathological variants were recorded and assessed. Treatment given and the status of the patients after the treatment were also noted wherever possible. A total of 421 cases of oral squamous cell carcinoma (OSCC) treated at our institute from August 2018 till December 2023 were identified. Out of these, there were 408 cases (97%) of conventional OSCC, while the remaining 13(3.1%) were the rare histopathological variants of conventional OSCC, which included 2 cases (0.5%) of acantholytic squamous cell carcinoma (ASCC), 7 cases (1.7%) of sarcomatoid squamous cell carcinoma (SSCC), and 4 cases (1%) of verrucous squamous cell carcinoma (VSCC). Both ASCC and SSCC showed poor prognosis despite adjuvant treatment in the form of CTRT, while VSCC showed good prognosis despite not receiving any adjuvant treatment. SSCC and ASCC are highly aggressive tumors, while VSCC has a good prognosis.

Introduction

Cancers of the lip and oral cavity are highly frequent in South Central Asia (e.g., India, Sri Lanka, and Pakistan) as well as Melanesia (Papua New Guinea, with the highest incidence rate worldwide in both males and females) reflecting the popularity of betel nut chewing. It is also the leading cause of death from cancer in India among men. Also, the incidence rates are high in Eastern and Western Europe and in Australia/New Zealand and have been linked to alcohol consumption, tobacco smoking, and HPV infection for cancers of the oropharyngeal region and to ultraviolet radiation from sunlight exposure for lip cancer [1]. Conventional oral squamous cell carcinoma (OSCC) is one of the most common cancers of the head and neck, and it has been categorized into well, moderately, and poorly differentiated variants by the current edition of the Classification of Head and Neck Tumors, which supports a simple grading system based on the Broder’s criteria for classifying conventional OSCC [2]. However, some rare variants of OSCC do exist, which include verrucous carcinoma(VC), acantholytic/adenoid/pseudoglandular SCC(ASCC)/sarcomatoid/spindle cell carcinoma (SSCC), adenosquamous carcinoma (ASC), basaloid SCC (BSCC), and papillary SCC (PSCC), each of which have a unique histomorphological appearance [3]. Here, we present a case series of different histopathological variants of conventional OSCC treated at our institute.

Materials and Method

A retrospective chart review was performed to search for squamous cell carcinoma of the oral cavity, which was operated at Rohilkhand Cancer Institute, Bareilly, Uttar Pradesh, India, from August 2018 till December 2023. Electronic database was searched for this purpose, and the histopathological variants of oral squamous cell carcinoma that underwent curative intent surgery including neck dissection, with or without adjuvant treatment, were included in the form of case series. Their age, gender, and subsite involved by tumor were recorded. Both major prognostic risk factors (extranodal extension, positive margins) and minor prognostic risk factors (tumor grade, lymphovascular invasion (LVI), perineural invasion (PNI), depth of invasion (DOI) ≥ 10 mm, bone invasion or skin invasion, positive nodes) were also recorded. IHC findings were also recorded if it had been. All these details were recorded from the patient’s histopathological reports. The histopathological slides were also re-evaluated by two independent pathologists, and the history of treatment received was recorded from the patient’s files. Last follow-up of each patient was recorded. Patients who had been coming for regular follow-up and were alive during their last follow-up were telephoned to find out whether they were alive or dead.

Results

A total of 421 cases of oral squamous cell carcinoma (OSCC) treated at our institute from August 2018 till December 2023 were identified. Out of these, there were 408 cases (97%) of conventional OSCC, while the remaining 13 (3.1%) were the rare histopathological variants of conventional OSCC, which included 2 cases (0.5%) of acantholytic squamous cell carcinoma(ASCC), 7 cases (1.7%) of sarcomatoid squamous cell carcinoma (SSCC), and 4 cases (1%) of verrucous squamous cell carcinoma (VSCC). The clinic-pathological details of these variants, treatment received, and the patient’s status after treatment are described as follows:

Acantholytic Squamous Cell Carcinoma (ASCC)

Hematoxylin and eosin (H and E) stained slides showed nests of malignant squamous epithelial cells, with areas having acantholysis of central cells and focal pearl formation giving a pseudoglandular appearance. Tumor cells at the periphery of nests had pleomorphism, enlarged, irregular hyperchromatric nucleus, densely eosinophilic cytoplasm, and frequent mitotic figures. Focal areas of typical squamous cell carcinoma were also present (Fig. 1). Clinico-pathological features of oral ASCC along with treatment given and the patients’ status after treatment are presented in Table 1. Both the patients received adjuvant CTRT. The 46-year-old male patient with ASCC left buccal mucosa expired after 4 months of treatment due to locoregional recurrence, while the other 41-year-old male with ASCC right buccal mucosa met death due to other cause.

Fig. 1.

Low power view showing acantholytic tumor cells(black arrow) and pseudoglandular appearance(red arrow)

Table 1.

Acantholytic variants of OSCC

Case	Age/gender	Site	Laterality	Histopathological risk factors present	pTNM	Treatment done and the patients’ status after treatment
1	46/Male	Buccal mucosa	Left	Tumor size = 4 cm DOI = 14 mm, skin involved WPOI type IV Close margin (3 mm) ENE present 1 positive node LNR = 0.03 (1/29)	pT4aN1	Composite resection +  MRND +  Adjuvant CTRT Expired 4 months post-surgery due to loco-regional recurrence
2	41/Male	Buccal mucosa	Right	Tumor size > 4 cm DOI = 9 mm Perineural invasion WPOI type IV 5 positive nodes ENE(> 2 mm) LNR = 0.3 (5/17)	pT3N3b	Bite composite resection +  MRND +  Adjuvant CTRT Died due to other cause

Sarcomatoid Squamous Cell Carcinoma (SSCC)

Hematoxylin and eosin (H and E)–stained slides showed invading tumor comprising of polygonal to spindle shaped cells. Tumor cells were large with moderate to marked nuclear pleomorphism, high N:C ratio, and nuclear hyperchromasia. Nuclei were elongated to ovoid in shape with fine nuclear chromatin and focal prominent nucleoli. There was brisk mitotic activity. Cytoplasm was scant to moderate in amount, deep eosinophilic with intra- and extracellular keratinization. Areas of hemorrhage and necrosis were present (Fig. 2). IHC was done for one case of SSCC which was immunopositive for cytokeratin and vimentin. The mean age of the patients with oral SSCC was 42.4 ± 2 years. Clinico-pathological features of these variants along with treatment given and the patient’s status after treatment are presented in Table 2. One of the patients of SSCC right buccal mucosa (44 years male) had tumor associated with major ENE (major risk factor) and also intraneural invasion, LVI and 12 positive nodes (minor risk factors). He was advised adjuvant CTRT but defaulted the treatment and thus developed loco-regional recurrence with second primary on the left buccal mucosa and expired within 3 months post-surgery. Another patient with SSCC right buccal mucosa (30 years male) had the tumor associated with minor risk factors only, which included tumor size > 4 cm, involvement of medullary spaces of the mandible, and 3 positive nodes. He also received adjuvant CTRT, but in spite of that, he developed distant metastasis 6 months post-surgery and hence administered palliative chemotherapy. The last dose of adjuvant RT had been given just 4 months back before he reported to us with distant metastasis. There was also a patient with SSCC floor of mouth (55 years male) with tumor associated with minor ENE (major risk factor) and minor risk factors including the presence of 6 positive nodes, tumor size > 4 cm, and skin involvement, and he was administered adjuvant CTRT. He had a disease-free interval of 1 year and 3 months, after which he developed locoregional recurrence and expired. One patient of SSCC right lower alveolus (55 years male) had tumor size > 4 cm, involvement of medullary spaces of the mandible and the skin, and one positive node, but he could not be given any adjuvant treatment as he met death due to other cause. Three other operated cases of oral SSCC were lost to follow-up.

Fig. 2.

Low power view showing invading tumor comprising of polygonal (red arrow) and spindle cells (black arrow)

Table 2.

Sarcomatoid variants of OSCC

Case	Age/gender	Site	Laterality	Histopathological risk factors present	pTNM	Treatment done and the patients’ status after treatment
1	44/M	Buccal mucosa	Right	DOI = 9 mm Lymphovascular invasion Intraneural invasion Close margin(3 mm) WPOI type IV 12 positive nodes ENE(> 2 mm) LNR = 0.52 (12/23)	ypT2N3b	Composite resection +  MRND Defaulted adjuvant treatment Expired 3 months post-surgery after development of second primary
2	30/M	Buccal mucosa	Right	Tumor size > 4 cm Medullary spaces of mandible involved WPOI type V 3 positive nodes LNR = 0.06 (3/48)	pT4aN2b	Composite resection +  MRND +  Adjuvant CTRT Developed distant metastasis 4 months after completing adjuvant treatment
3	55/M	Floor of mouth	Anterior (involving midline)	Skin involved WPOI type IV 6 positive nodes ENE present (≤ 2 mm) LNR = 0.094 (6/64)	pT4aN3b	Composite resection  + Bilateral MRND + Adjuvant CTRT Expired 1 and a quarter year post-surgery
4	55/M	Lower alveolus Involving floor of mouth	Right (midline involved anteriorly in the region of floor of mouth)	Tumor size > 4 cm Involvement of medullary spaces of mandible Skin involved WPOI type V 1 positive node LNR = 0.02 (1/57)	pT4aN1	Composite resection  + MRND Died due to other cause
5	48/M	Buccal mucosa	Right	DOI = 10 mm WPOI type IV	pT2N0	Composite resection  + MRND Lost to follow-up
6	30/M	Lower alveolus	Left	Tumor size > 4 cm Skin involved WPOI type IV 1 positive node LNR = 1.9 (1/54)	pT4aN1	Composite resection + Bilateral MRND Lost to follow-up
7	35/M	Lower alveolus	Left	Tumor size > 4 cm Involvement of medullary spaces of mandible Perineural invasion WPOI type V 3 positive nodes ENE present (≤ 2 mm) LNR = 0.11 (3/27)	pT4b N3b	Bite composite resection +  MRND Lost to follow-up

Verrucous Squamous Cell Carcinoma (VSCC)

Hematoxylin and eosin (H and E)–stained slides showed squamous cell carcinoma with mild atypia and broad rete pegs pushing into the underlying stroma. Parakeratotic plugging was seen. Lymphocytes and plasma cells were also present. No definitive invasion seen. Low mitotic activity was present (Fig. 3a,b). Clinico-pathological features of oral VSCC along with treatment given are presented in Table 3. None of the cases of VSCC were given any adjuvant treatment, even though two cases had minor prognostic risk factors. One had a close margin of 3 mm, while the other had tumor size > 4 cm. In spite of not receiving any adjuvant treatment, none developed recurrence or distant metastasis, but they were kept under close observation.

Fig. 3.

a Low power view showing rete pegs (black arrow) pushing into the underlying stroma. b Low power view showing parakeratotic plugging (black arrow)

Table 3.

Verrucous variants of OSCC

Case	Age/gender	Site	Laterality	Histopathological risk factors present	pTNM	Treatment done and the patients’ status after treatment
1	60/Male	Buccal mucosa	Left	None	pT1N0	Wide local excision +  Marginal mandibulectomy +  SOHND No evidence of recurrences or distant metastasis
2	36/Male	Buccal mucosa	Left	Close margin (3 mm)	pT2N0	Wide local excision +  Marginal mandibulectomy +  SOHND No evidence of recurrences or distant metastasis
3	35/Male	Buccal mucosa	Left	None	pT2N0	Wide local excision +  Marginal mandibulectomy +  MRND No evidence of recurrences or distant metastasis
4	40/Male	Lower alveolus	Left	Tumor size > 4 cm	pT3N0	Wide local excision +  Marginal mandibulectomy +  SOHND No evidence of recurrences or distant metastasis

Discussion

Conventional oral squamous cell carcinoma (OSCC) is one of the most common cancers of the head and neck region [2]. Ninety-seven percent of OSCC operated at our institute were conventional. The rare histopathological variants treated at our institute were acantholytic squamous cell carcinoma (ASCC), sarcomatoid squamous cell carcinoma (SSCC), and verrucous squamous cell carcinoma (VSCC), and they constituted 3.1% of all OSCCs.

Acantholytic squamous cell carcinoma (ASCC) is an uncommon but well-recognized variant of squamous cell carcinoma that was first described by Lever in 1947 [4]. It arises most commonly in areas of the skin exposed to the sun. It is also known as pseudoglandular squamous cell carcinoma, squamous cell carcinoma with glandlike (adenoid) features, pseudovascular adenoid squamous cell carcinoma, adenoid squamous carcinoma, angiosarcoma-like squamous cell carcinoma, adenoacanthoma, and pseudoangiosarcomatous carcinoma. It differs from common squamous cell carcinoma in terms of histopathological features and its aggressive nature. It is also differentiated from adenocarcinomas particularly, adenosquamous carcinomas by absence of true glandular formations and negativity for mucin stains. ASCC can mimic adenoid cystic carcinomas due to the presence of glandular spaces and fibrin in these spaces may masquerade as mucin [5]. In the oral cavity, ASCC is extremely rare, accounting for fewer than 4% of all occurrences [6]. Abba et al. found tongue (24/55) and the maxilla/maxillary gingiva and/or palate (11/55) as the most common sites to be involved by ASCC. Based on the data available with them, they found no evidence that would suggest that ASCC is more aggressive than conventional SCC in intraoral regions [7]. However, this tumor is reported to have a diverse biologic behavior, because of which it can metastasize to distant places, thus leading to poor prognosis. There is a slight masculine predisposition, with lower lip being most commonly affected [6]. At our institute also they were found merely in male patients, with an incidence of 0.5%, and they were found in the buccal mucosa. They were also associated with histopathological risk factors, and adjuvant treatment was given post-surgery. Both the patients of oral ASCC operated at our institute received adjuvant CTRT post-surgery. One of the patients died 4 months after the treatment due to disease, while the other died due to some other cause.

Sarcomatoid squamous cell carcinoma (SSCC) comprises a diverse collection of benign and malignant tumors. It is a rare and peculiar biphasic malignant neoplasm. It is a variant of squamous cell carcinoma having spindled or pleomorphic tumor cells that simulate a true sarcoma, but are epithelial in origin. It can also be called as carcinosarcoma, pseudosarcoma, spindle cell carcinoma, pleomorphic carcinoma, polypoid carcinoma, pseudosarcomatous carcinoma, metaplastic carcinoma, and Lane’s tumor. The initial description of this kind of malignancy was reported in 1864 by Virchow, who called it as carcinosarcoma. However, it was Krompecher who proposed the theory that carcinoma cells have the ability to undergo sarcomatous transformation. However, the term “spindle cell carcinoma” was first applied by Shervin et al. It is an unusual aggressive variant that frequently recurs and metastasizes, reinforcing the importance of its correct diagnosis [8]. It usually occurs in the urinary tract and upper respiratory tract in elderly men and is rarely found in the maxillofacial region [9]. In the head and neck regions, it is most frequently encountered in the larynx [10, 14] It also occurs in the nasal cavity, hypopharynx, oral cavities, esophagus, trachea, skin, and breast [10]. Incidence is < 1% of all tumors of oral cavity [11]. SSCC of the oral cavity presents a male predominance, and mean ages of occurrence as 52.8, 57, and 65.7 years have been reported [12–14]. There is site predilection for the lower lip, tongue, and alveolar ridge or gingiva [8, 12, 14]. At our institute, they comprised 1.7% of all OSCCs and occurred only in male patients with the age ranging from 30 to 55 years, with a mean age of 42.4 years. Buccal mucosa and lower alveolus were the most common subsites to be involved by oral SSCC. However, floor of the mouth was also involved in some cases.

Better understanding of the nature of sarcomatoid carcinoma could help in the selection of appropriate therapies to hinder its progression. A number of different histogenetic theories have been developed over the years, with a few principal theories; firstly, a separate epithelial and mesenchymal cell, each of which that become malignant (carcinosarcoma or collision tumor); secondly, an epithelial cell that differentiates into both squamous as well as spindle cell components (spindle cell carcinoma); thirdly, a carcinoma stimulating a benign reactive stromal response(carcinoma with pseudosarcoma), and lastly, a malignant epithelial cell that “dedifferentiates” into a sarcoma(carcinosarcoma). Although it may be difficult to prove any of these theories, evidence is in favor of an epithelial cell that differentiates into both a carcinoma and a spindle cell component, the latter still maintaining epithelial differentiation no matter how meager. This supported by the evidences such as their occurrence in the exact sites that normally have squamous epithelium and a preponderance of carcinomas rather than sarcomas; a superficial location; a polypoid appearance; the direct continuity and smooth transition of the spindled cells with areas of squamous epithelium, be it benign, dysplastic, or frankly carcinomatous (even if the transition zone is frequently indistinct due to surface ulceration or necrosis); immunoreactivity with epithelial antigens; a dual expression of epithelial and mesenchymal differentiation with double labeling techniques in some neoplastic spindle cells; and the presence of only epithelial cells or only sarcomatous cells or a duality of expression in metastatic deposits from laryngeal SSCC [15].

Differential diagnosis of SSCC includes a number of benign and malignant processes, such as fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, malignant peripheral nerve sheath tumor, osteosarcoma, mesenchymal chondrosarcoma, Kaposi’s sarcoma, angiosarcoma, synovial sarcoma, malignant melanoma, fibromatosis, leiomyoma, nodular fasciitis, and reactive epithelial proliferations. It is easy to see how the magnitude of diagnostic differentials can be a source of frustration for the pathologist [15]. These tumors are immune-positive for cytokeratin and vimentin [8, 14, 16, 17]. Cytokeratins are a family of water-insoluble proteins forming a major part of the cytoskeleton of epithelial cells and thus forms an important aid in the classification of epithelial neoplasm. Vimentin on the other hand is the major intermediate filament in a variety of mesenchymal cells [14]. Hence, IHC has revealed that the squamous cell carcinoma component is strongly positive for cytokeratin. On the other hand, the spindle cells have been found to be focally positive for cytokeratin and epithelial membrane antigen and strongly positive for vimentin [17]. By IHC analysis spindle cell sarcoma, melanoma and malignant myoepithelioma can be ruled out [14]. At our institute, IHC was done for the first operated case of SSCC, which was immunopositive for cytokeratin and vimentin. In rest of the patients, it could not be done as these patients could not afford for the same. It was also not essential because of the presence of epithelial components [16]. The behavior of SSCC is more aggressive than that of conventional SCC at a similar stage. Setting wider safety margins (> 2 cm) during surgical intervention is recommended. In the case of locoregional recurrence, salvage operation shows benefit. Seeking an effective chemotherapy protocol is important for the control of distant recurrence [10]. Our patients of oral SSCC who turned up for follow-up post-surgery were administered adjuvant treatment.

Verrucous carcinoma is a form of squamous cell carcinoma possessing specific clinical, morphologic, and cytokinetic features. It refers to exophytic squamous mucosal or cutaneous tumors that are heaped above the epithelial surface with a papillary micronodular appearance. They may be found on cutaneous surfaces including the anorectal region, penis, vagina, and skin of the extremities, particularly the sole of the foot [18]. Oral verrucous carcinoma accounts for 0.57–16.08% of OSCCs and is predominantly found in males with the reported mean age at diagnosis between 49 and 69.5 years. At our institute, their incidence was 1%, and they occurred in the buccal mucosa of the males.

Verrucous papillary lesions were first reported on the buccal mucosa in eight tobacco chewers by Friedell and Rosenthal in 1941. Seven years later, Ackerman described histopathologic and clinical features of this neoplasm and defined it as a distinct clinicopathologic entity and introduced a term verrucous carcinoma. In spite of having low mitotic activity and slow growth, it can infiltrate adjacent tissues in advanced stages but does not metastasize. Differential diagnosis includes verrucous hyperplasia, proliferative verrucous leukoplakia, oral squamous papilloma, oral verrucous carcinoma, and hybrid oral verrucous carcinoma to conventional oral SCC with an exophytic growth pattern [19]. Buccal mucosa is the most common primary site involved by this tumor [20, 21]. In our case series also, all the cases of verrucous carcinoma were in the buccal mucosa.

Enlargement of draining lymph nodes in oral VSCC is common and represents reactive hyperplasia secondary to the inflammatory reaction at the tumor’s stromal interface[18]. Initial reports of neck metastasis in verrucous carcinoma are believed to be caused by incorrect pathologic diagnosis or by the presence of foci of conventional SCC of varying degree of differentiation within a verrucous carcinoma. At our institute, wide local excision and marginal mandibulectomy was performed along with neck dissection. Since histologically pure oral verrucous carcinoma does not metastasize, END is usually not needed during primary surgery but is indicated in hybrid oral verrucous carcinoma and when microvascular flap is used for reconstruction of tumor defect [19]. We would also not recommend END for verrucous carcinoma as there was no positive neck node found histologically.

Wide surgical excision is usually considered the treatment of choice, but there is on there is ongoing debate about the optimal width of surgical margins and the need for elective neck dissection (END). Similar to conventional oral SCC, clinical surgical margin of 10–15 mm and histological margin of at least 5 mm are still considered enough to not increase the risk of local recurrence of oral verrucous carcinoma, although no worse outcomes were reported in patients with close histological margins (i.e., less than 5 mm) who did not receive adjuvant radiotherapy [19]. None of the cases of oral VSCC operated at our institute received adjuvant treatment, even though one had a close margin of 3 mm. One patient also had tumor size of more than 4 cm, but all margins were free. In spite of not receiving any adjuvant treatment, these patients did not show any evidence of recurrence nor did they develop any distant metastasis. Studies have reported poor response to initial course of radiotherapy, with a sudden alteration of the character of the lesion to an anaplastic pattern, due to which the lesion grows rapidly, with distant metastasis, leading to death [21]. Complete response to radiotherapy has also been reported [20]. However, a recent study found no clear survival benefit with adjuvant radiotherapy, and surgery alone with negative margins was suggested as the optimal treatment for patients with oral cavity VSCC [22].

The use of chemotherapy for the treatment of VSCC has also been described with encouraging results using methotrexate as a primary therapy [23, 24]. Preliminary observations in two elderly patients showed well tolerance with capecitabine, an oral fluoropyrimidine. It can also induce rapid, clinically significant response. Although not curative, it may provide a cost-effective alternative for elderly patients with a significant improvement in their quality of life [25]. The use of various other non-surgical techniques such as cryotherapy, photodynamic therapy (PDT), and CO2 laser has also been described [19].

Conclusion

Sarcomatoid squamous cell carcinoma is a highly aggressive tumor associated with various histopathological risk factors associated with poor prognosis. Acantholytic squamous cell carcinoma has also been found to be aggressive, but there are varied results when compared to conventional oral squamous cell carcinoma. Both these tumors are associated with infiltrative patterns of invasion, and almost all of them have histopathological risk factors associated with poor prognosis, and they require adjuvant treatment post-surgery. On the other hand, verrucous carcinoma is hardly associated with any histopathological risk factors associated with poor prognosis, and the pattern of invasion found is also generally non-infiltrative. The use of radiotherapy in these tumors is controversial. If cases of verrucous carcinoma are associated with minor prognostic risk factors, it is better to keep them under close observation rather than considering them directly for adjuvant radiotherapy, which can worsen the case rather than improving it. We did not find any recurrences in our case series, in spite of the fact that verrucous oral squamous cell carcinoma cases with tumor size > 4 cm or close margin of 3 mm did not receive any adjuvant radiotherapy. Based on the findings of our study, acantholytic variant of oral squamous cell carcinoma is extremely rare (0.5%), followed by verrucous (1%) and sarcomatoid variants (1.7%). All these variants have a male predilection, and they usually involve the buccal mucosa.

Funding

No funds, grants or other support was received.

Declarations

Ethical Approval

The study was approved by the Institutional Review Board of Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh, India.

Informed Consent

Not required.

Conflict of Interest

The authors declare no competing interests.