Oral Oncology xxx (xxxx) xxx

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Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

Letter to the editor

Spindle cell squamous cell carcinoma of alveolus with heterologous mesenchymal differentiation
and synchronous contralateral buccal squamous cell carcinoma in a background of oral
submucous fibrosis: Recapitulation of embryonic plasticity?

A forty nine years old male patient presented with a chief complaint only pan-cytokeratin and p63. Their expression was also seen focally in
of reduced mouth opening and swelling in the left lower back tooth the spindle cell component (Fig. 3a–d). In contrary, vimentin was
region. The patient had a history of pan chewing for around fifteen expressed diffusely in the spindled cells with no immunoreactivity in
years. On examination, an exophytic polypoid mass was noted on the left epithelium (Fig. 3e–f). There was expression of SMA, p53 and SATB2 in
lower partially edentulous alveolus distal to tooth number 33 with an spindle cells; p53 was also focally expressed in epithelial portion. Pro­
extension to left buccal mucosa measuring approximately 3.5 × 3 cm. liferation index as semi quantified by Ki-67 was over 90%. S100 was
There was a restricted mouth opening of 17 mm with diffuse pallor of the only expressed by the chondrocytes (Fig. 4a–f). Desmin and CD34 were
entire oral mucosa including the palate. Another speckled lesion negative in the tumor cells (not shown). Correlating histomorphologi­
measuring 0.8 × 0.4 cm was noted on the right buccal mucosa close to cally and immunohistochemistry, left alveolar tumor was diagnosed as
the right commissure of the mouth. Owing to restricted mouth opening, spindle cell squamous cell carcinoma (SCSCC).
an incisional biopsy could not be made from the left alveolus, thus the Lesion of the right buccal mucosa showed residual superficially
buccal mucosae of both sides were biopsied and was reported as well invasive squamous cell carcinoma with a DOI of 1 mm (Fig. 2b–c).
differentiated squamous cell carcinoma arising in advanced oral sub­ Bilaterally, the lymph nodes were free of metastatic deposits but mul­
mucous fibrosis. There were multiple enlarged lymph nodes in right tiple lymph nodes of right levels IIA, III and IV showed multiple case­
levels II to IV. After extensive discussion in the tumor board, wide local ating granuloma and multinucleated Langhans type giant cells
excision of lesions of both sides with bilateral selective neck dissection suggestive of tuberculous lymphadenopathy (Fig. 2d). Final tumor
was planned with reconstruction. Intra-operatively, all resected and staging was pT2 (2) N0 M0 (AJCC 8th edition). The patient is under
revised margins were free of tumor. routine follow-up.
Sections from the resected specimen of left side showed an ulcerated Oral squamous cell carcinoma (OSCC) is the sixth most common
invasive epithelial neoplasm of epithelial origin composed of invading malignant neoplasm, and is considered to be a major cause of mortality
large superficial tumor islands with an abrupt transition to spindle cell globally despite of advancement in the treatment and diagnostic mo­
component (Fig. 1a–c). The spindle cell component showed streaming dalities [1,2]. Amongst the poor outcome measures of OSCC, histologi­
fascicles of moderately pleomorphic spindly cells with indistinct cell cal variant is an important factor in addition to pattern of invasion, LVE,
outlines and enlarged pleomorphic vesicular nuclei. The mitotic count PNI, nodal metastasis and extranodal extension. SCSCC a rare histo­
was 6-7 MF/HPF. Additionally, there was heterologous mesenchymal logical variant of squamous cell carcinoma. Since the time this tumor
differentiation in the form of hyaline cartilage (chondroid) and malig­ was first introduced in 1864 as ‘carcinosarcoma’, the nomenclature has
nant tumor osteoid which appeared to calcify at areas (Fig. 1e–f). The changed over years and the term ‘spindle cell squamous cell carcinoma’
tumor cells at invasive front were in the form of single cells (Fig. 2a). is preferred in the latest WHO classification of head and neck tumors
Vascularity and inflammatory reaction were moderate, with no lym­ [3,4]. Very rarely, SCSCC shows heterologous mesenchymal differenti­
phovascular embolisation (LVE), perineural invasion (PNI) or infiltra­ ation in the form of malignant bone, skeletal muscles or cartilage. Till
tion into skeletal muscles/underlying bone. Depth of invasion (DOI) was date only seven cases have been described in the oral cavity with true
9 mm. Immunohistochemically, the epithelial component expressed mesenchymal differentiation however, most cases lacked complete

https://doi.org/10.1016/j.oraloncology.2021.105476
Received 27 July 2021; Accepted 28 July 2021
1368-8375/© 2021 Elsevier Ltd. All rights reserved.

Please cite this article as: Deepak Pandiar, Oral Oncology, https://doi.org/10.1016/j.oraloncology.2021.105476
Letter to the editor Oral Oncology xxx (xxxx) xxx

Fig. 1. Photomicrographs of H&E stained sections showing superficial epithelial component with abrupt transition to fascicles of spindle cells (a–c) and heterologous
mesenchymal differentiation in the form of malignant bone and cartilage (d–f) (a, b, d, e, f 40× and c, 100×).

clinicopathological profile and treatment modalities making it impos­ (EMT)-type 2 might play a role instead of usual EMT-type 3 of malignant
sible to draw any conclusion regarding the effect of such differentiation neoplasm showing overt metastatic potential [8]. Additionally, there is
on the tumor outcome [5]. In the present case, the spindle cells showed phenotypic switch from reduced expression of e-catherin to increased n-
smooth muscle, chondroid and bony differentiation. catherin expression. EMT is a complex procedure where the epithelial
The present case is unique as synchronous spindle cell squamous cell cells switch to functions and characteristics of mesenchymal cells by
carcinoma and conventional SCC in a background of OSMF have not undergoing a loss of cell-to cell adhesions with alteration in cytological
been reported so far to the best of our knowledge. In general, it has been polarity and reorganization [9]. As in the present case, where synchro­
hypothesized that accumulation of carcinogens aided by stromal fibrosis nous malignancies arose in a background of advanced OSMF, there
and reduced vascularity affects the compromised epithelium in OSMF could be switch in EMT from type 2 to type 1 leading to generation of
which results in acquisition of dysplastic features and malignant trans­ spindle cells bearing properties of mesenchymal stromal cells (MSCs)
formation [6]. Also it is speculated that most cases of SCC arising in with a cartilage or bone forming potential [10]. Similar phenomenon
OSMF (SCC-OSMF) are low grade with limited potential for metastasis. has been shown by vascular endothelial cells by which endothelial
OSMF has also been considered as an over-healing wound [7]. Thus mesenchymal transition lead to generation of bone and cartilage [10].
during malignant transformation, epithelial mesenchymal transition These phenomena demonstrate that during malignant transformation

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Letter to the editor Oral Oncology xxx (xxxx) xxx

Fig. 2. Photomicrographs of H&E stained sections showing invasive front (a 100×), (b–c) tumor of right sight with advanced OSMF (40×) and tuberculous node
(d 40×).

from epithelium to mesenchymal stromal like cells with heterologous the oral cavity, there was no evidence of metastasis.
potential of trans-differentiation, there is recapitulation of embryonic In conclusion, OSCC arising in oral submucous fibrosis, a generalized
plasticity [10]. potential malignant condition, appears to be low grade carcinomas with
As previously demonstrated, p53 was expressed both in epithelial a limited chance of neck dissemination. They behave differently from
and spindle cell components supporting their monoclonal origin [5]. conventional squamous cell carcinoma. In our experience of OSCC-
Another marker of particular interest in our case was diffuse nuclear OSMF cases, it has been observed that these tumors show rare nodal
expression of SATB2. As aforementioned the synchronous malignancies metastasis and thus are excellent model for unique and unexplored
in the present case arose in a background of advanced OSMF, which is associated mechanisms.
generally considered to be a hypoxic state with reduced vascularity. It
was recently demonstrated that under hypoxic conditions, the expres­ Declaration of Competing Interest
sion of SATB2 in OSCC cell lines was significantly increased [11]. The
authors concluded that SATB2 knockdown suppressed the hypoxia‑in­ The authors declare that they have no known competing financial
duced autophagy and stemness properties with resultant reduced pro­ interests or personal relationships that could have appeared to influence
liferative, invasive and migratory capabilities [11]. Thus OSCC (SCSCC the work reported in this paper.
in present scenario) arising in OSMF might have limited potential for
nodal metastasis aided by stromal fibrosis and behave like low grade
malignancies as seen in our case where despite extensive involvement of

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Letter to the editor Oral Oncology xxx (xxxx) xxx

Fig. 3. Photomicrographs of IHC stained sections showing positivity for pancytokeratin (a- in the epithelial component, b- in the spindle cells), p63 (c- in the
epithelial component, d- in the spindle cells) and vimentin (e- in the epithelial component, f- in the spindle cells).

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Letter to the editor Oral Oncology xxx (xxxx) xxx

Fig. 4. Photomicrographs of IHC stained sections showing (a) SMA positivity in spindle cells, (b) diffuse nuclear positivity for SATB2 in tumor cells, (c) S100
positivity in chondrocytes, (d) Ki-67 index of >90%, (e) partial p53 expression in epithelial component and (f) diffuse expression of p53 in spindle cells.

References submucous fibrosis and oral squamous cell carcinoma. Jpn Dent Sci Rev 2020;56
(1):97–108.
[9] Pandiar D, Nayanar SK, Ankalkoti B, Babu S. Laryngeal basaloid squamous cell
[1] Anand R, Pandiar D, Kamboj M. Financial burden of oral squamous cell carcinoma
carcinoma with a substantial spindle cell component: case presentation and
in India. Oral Oncol 2020;103(Apr).
updated review of literature. Head NeckPathol 2019;13(4):692–8.
[2] Pandiar D, Ramani P, Krishnan RP, Monica K. Multifaceted multinucleated giant
[10] Shoshani O, Zipori D. Transition of endothelium to cartilage and bone. Cell Stem
cells in oral squamous cell carcinoma. Oral Oncol 2021. https://doi.org/10.1016/j.
Cell 2011;8(1):10–1.
oraloncology.2021.105400. Epub ahead of print.
[11] Dong W, Chen Y, Qian N, Sima G, Zhang J, Guo Z, et al. SATB2 knockdown de­
[3] Mahajan A, Mohanty S, Ghosh S, Urs AB, Khurana N, Gupta S. Sarcomatoid car­
creases hypoxia-induced autophagy and stemness in oral squamous cell carcinoma.
cinoma of the oral cavity: a diagnostic dilemma. Case Rep Dent 2017;2017:1–6.
Oncol Lett 2020;20(1):794–802.
[4] El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO classification of
head and neck tumours, 4th ed. Lyon: IARC; 2017. p. 110 [chapt. 4].
[5] Ono S, Makino T, Yanai H, Kawai H, Takabatake K, Nakano K, et al. A case report of Deepak Pandiar, MDS, PhD, Pratibha Ramani, MDS, PhD, DNB*,
spindle cell carcinoma with osteoid and cartilage formation in the tongue. Reports
2021;4(1):5. https://doi.org/10.3390/reports4010005.
Reshma Poothakulath Krishnan, MDS, Snega Thamilselvan, BDS, Deepa
[6] Pandiar D, Shameena P. Immunohistochemical expression of CD34 and basic R. Viswasini, BDS
fibroblast growth factor (bFGF) in oral submucous fibrosis. J Oral Maxillofac Department of Oral Pathology and Microbiology, Saveetha Dental College
Pathol 2014;18(2):155–61.
and Hospitals, Chennai, Tamil Nadu, India
[7] Sharma M, Shetty SS, Radhakrishnan R. Oral submucous fibrosis as an overhealing
wound: implications in malignant transformation. Recent Pat Anticancer Drug
Discov 2018;13(3):272–91. *
Corresponding author.
[8] Shetty SS, Sharma M, Fonseca FP, Jayaram P, Tanwar AS, Kabekkodu SP, et al.
Signaling pathways promoting epithelial mesenchymal transition in oral
E-mail address: dr_pratibha@rediffmail.com (P. Ramani).