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Knowing the unknown in oral squamous cell carcinoma: An observational study

1 Department of Oral Anatomy, Postgraduate Institute of Dental Sciences, Rohtak, Haryana, India
2 Department of Oral Pathology, Postgraduate Institute of Dental Sciences, Rohtak, Haryana, India

Date of Submission27-Dec-2018
Date of Acceptance09-Jun-2019
Date of Web Publication06-Feb-2020

Correspondence Address:
Shruti Gupta,
H. No. 166, Old PLA Sector, Hisar - 125 001, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_898_18

 > Abstract 

Introduction: Conventional oral squamous cell carcinoma (OSCC) is relatively easy to diagnose on histopathology, as it comprises dysplastic epithelial cells with variable degrees of squamous differentiation. Different grading systems have been employed in grading OSCC based on its dysplastic features and host response. Some unusual features such as clear cell change, epithelial–mesenchymal transition (EMT), stromal hyalinization, stromal desmoplasia, perineural invasion, vascular invasion, tissue eosinophilia, giant cells, and tertiary lymphoid follicle formation are evident in OSCC histologically but have not yet been accounted in any grading systems of OSCC except perineural and vascular invasion.
Aim: The aim of the present study was to identify these uncommon features and to correlate them with different grades of OSCC.
Materials and Methods:This study was conducted on 100 histopathologically confirmed OSCC cases retrieved from the archives of our department. They were graded on the basis of Broder's grading system and were reviewed for the features mentioned above. Data collected were subjected to statistical analysis.
Results: Clear cell change, EMT, foreign body giant cells, and tumor giant cells were observed in 13%, 20%, 1%, and 3% of cases, respectively. We found stromal desmoplasia in 15% and stromal hyalinization in 9% of cases. Tissue eosinophilia, tertiary lymphoid follicle formation, and perineural invasion were observed in 12%, 3%, and 2% of cases, respectively. Vascular invasion was not evident in any of the cases examined.
Conclusion: The incidence of the unusual features was 7.8% in our study.

Keywords: Clear cell change, desmoplasia, epithelial–mesenchymal transition, giant cells, oral squamous cell carcinoma, tertiary lymphoid follicle

How to cite this URL:
Gupta S, Kamboj M, Narwal A. Knowing the unknown in oral squamous cell carcinoma: An observational study. J Can Res Ther [Epub ahead of print] [cited 2022 Aug 7]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=277831

 > Introduction Top

Oral squamous cell carcinoma (OSCC) is the sixth-most common cancer, with an annual incidence of over 30,000 cases reported globally, of which majorly 62% arise in developing countries.[1] It is considered an aggressive lesion because of its hallmark locoregional invasion and metastasis to cervical lymph nodes, thus confirming its link with severe morbidity, decreased survival rates, and high rate of recurrence.[2],[3] Conventional OSCC is relatively easy to diagnose on histopathology, as it is comprised of dysplastic epithelial cells with variable extent of squamous differentiation.[4] Many authors have proposed different histological classification systems to determine the grade of OSCC on the basis of the presence of dysplastic features and host response. These histological classification systems are not only of academic interest but also help in deciding treatment and its prognosis.[5] While diagnosing OSCC based on its dysplastic features, usually, some unusual traits such as clear cell change, epithelial–mesenchymal transition (EMT), stromal hyalinization, stromal desmoplasia, perineural invasion, vascular invasion, tissue eosinophilia, giant cells, and tertiary lymphoid follicle formation are encountered but not reported or mentioned in our histopathological reports. On literature search, we found that, except perineural and vascular invasion, none of these unusual features have been accounted in the grading systems of OSCC, and their role in determining the prognosis remains a mystery. Therefore, a study is required which should evaluate these unusual features in OSCC and correlate them with the histological grades of OSCC so that if any significant association is found between these unusual features and histological grades of OSCC, a newer histological grading system could be proposed which could customize cancer treatment and depict its prognosis. Till date, no study has reported the incidence of these unusual features collectively in OSCC. Therefore, ours is the first study which recorded the incidence of these unusual features in our hospital and related them with the histological grades of OSCC collectively.

Aim and objectives

The aim of the present study was to determine the role of these unusual attributes in the grading and prognosis of OSCC. The objectives were (i) to record these uncommon features in OSCC and (ii) to correlate them with the histological grades of OSCC.

 > Materials and Methods Top

The present retrospective study comprised 100 cases of histologically confirmed OSCC retrieved from the archives of our department. Demographic data and the histological grading for each case were recorded from the archival data. Tumor grade was established according to the degree of keratinization and cell dedifferentiation according to Broder's grading system, and the slides were graded as well-differentiated SCC, moderately differentiated SCC, and poorly differentiated SCC. Each case was then reviewed by three histopathologists for the unusual features (clear cell change, EMT, stromal hyalinization, stromal desmoplasia, perineural invasion, vascular invasion, tissue eosinophilia, giant cells, and tertiary lymphoid follicle formation), and the case was considered positive for a feature when out of three, two histopathologists confirmed the presence of the feature in that particular case. The data collected were subjected to statistical analysis. Fisher's exact test was applied to find the relation between these unusual features and histological grading of OSCC.

 > Results Top

The present study comprised 100 cases of OSCC, out of which 76 were male and 24 were female. The most predominantly affected age group in our study was 51–60 years (34%) followed by 61–70 years (27%), 41–50 years (16%), >71 years (13%), and <40 or 40 years (10%).

On the basis of histological grading, majority of cases in the present study were of well-differentiated OSCC (68%) followed by moderately (30%) and poorly differentiated OSCC (2%).

Clear cell change, EMT, tissue eosinophilia, and perineural invasion were observed in 13%, 20%, 12%, and 2% of cases, respectively. We found stromal desmoplasia in 15% and stromal hyalinization in 9% of OSCC cases. Foreign body giant cells, tumor giant cells, and tertiary lymphoid follicle formation were observed in 1%, 3%, and 3% of cases, respectively. We did not find vascular invasion in any of the cases. A significant relation was found between the histological grades of OSCC and clear cell change only, whereas no significant relation was found between histological grades and other unusual features [Table 1].
Table 1: Distribution and relation of unusual features according to histology

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 > Discussion Top

The host tissue stroma plays an important role in the maintenance of both normal epithelial tissues and their malignant counterparts. Even though most stromal host cells possess certain tumor-suppressing capabilities, the stromal changes that will occur during malignancy in due course of time promote growth, invasion, and metastasis.[6] The role of some of these alterations occurring in stroma during malignancy is not very clear; hence, this study was an attempt to establish the effect of these features on the treatment and prognosis of OSCC.

Epithelial–mesenchymal transition

EMT is a “biological process in which an epithelial cell undergoes multiple biologic metamorphosis to a mesenchymal phenotype” due to reorganization of its cytoskeleton and breaking its contact with neighbors. Due to this change, epithelial cells “acquire increased resistance to apoptosis, improved migratory capacity, and invasiveness.”[7],[8] Morphologically, cancer cells which undergo EMT change their cobblestone-like, noninvasive epithelial characteristics to elongated, motile, and invasive mesenchymal features.[8] Based on biological and biomarker types, EMT has been classified into three categories including type I EMT in embryogenesis; type II in organ fibrosis, wound healing, and regeneration of tissue; and type III EMT is associated with cancer progression and metastasis.[7],[8] In cancer specimens exhibiting type III EMT, several markers of EMT have been related with the presence of metastasis, decrease in survival rate, and increase in recurrence rate. This supports the concept that several events taking place in type III EMT represent aggressive behavioral changes of cancer cells.[8] However, some studies stated that the role of EMT in cancer is controversial as there is no evidence of EMT in cancer metastasizing in vivo. They also reported that EMT/mesenchymal–epithelial transition is “a laboratory artifact and it is not significant to exert clinical effort to understand and control these epithelial–stromal interactions that occur during carcinogenesis, invasion, and metastasis in humans.”[9] In the present study, EMT was observed in 20% of cases; however, we did not find any significant relation between EMT and histological grades of OSCC [Figure 1]a.
Figure 1: (a) Epithelial–mesenchymal transition of the tumor cells (H and E stain, ×40; ×10 [inset]) (b) tertiary lymphoid follicles (H and E stain, ×4)

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Stromal desmoplasia

According to Haneke, desmoplastic SCCs are characterized by the presence of “fine branches of tumor cells at the periphery which are surrounded by a desmoplastic stromal reaction.”[10] Stromal desmoplasia is characterized by the reaction of the host cells in the form of dense deposition of extracellular matrix and proliferation of fibroblasts to the inductive stimuli exerted by the tumor cells.[6],[11] The biological relevance of desmoplasia in SCCs is still not clear. Earlier, it was suggested that this response acts as a defense mechanism to prevent tumor growth; however, during recent years, it has been increasingly unveiled that “the crosstalk between the cancer cells and the tumor stroma is highly responsible for the progression of tumors and their metastasis.”[6],[12] In our study, we found stromal desmoplasia in 15% of OSCC cases, and most of them were well-differentiated SCC [Figure 2]a. Kawashiri et al. in their study on OSCCs reported that “fibrous stroma in SCC appeared to have a desmoplastic response, with tumor desmoplasia occurring in highly developed, invasive tumors.”[11] Breuninger et al. reported that, out of 594 SCCs of skin and vermillion surface, 44 (7.4%) were desmoplastic. A majority of desmoplastic SCCs in their study were found in SCCs having middle differentiation (61.4%) followed by low (27.2%) and high differentiation SCCs (11.4%).[10] Sis et al. in their study on colorectal carcinomas reported that desmoplasia measured by image analysis could act as a significant prognostic indicator.[12]
Figure 2: (a) Stromal desmoplasia (H and E stain, ×4; ×10 [inset]); (b) stromal hyalinization (H and E stain, ×10; ×10 [inset])

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Stromal hyalinization

Stromal hyalinization is illustrated as homogenous eosinophilic condensation of collagen with the presence of less number of cells. It is considered an attempt of the host cells to wall off the invasive tumor cells.[4] In our study, stromal hyalinization was found in 9% of cases, of which five cases were of well-differentiated SCC [Figure 2]b.

Perineural invasion

Perineural invasion is defined as a “tropism of tumor cells for nerve bundles in the surrounding tissues.”[13] It is regarded as an independent factor in determining the poor prognosis in salivary gland malignancies and colorectal carcinoma. However, there is no single agreement among authors regarding its effect on the prognosis of OSCC.[13],[14] In our study, we found perineural invasion in 2% of cases only [Figure 3]. However, Varsha et al. in their study found perineural invasion in 40.5% of OSCC cases.[3] Jardim et al. in their study on SCC of tongue and floor of mouth found perineural invasion in 50% of cases.[13] This difference could be attributed to the fact that most of the cases in our study were incisional biopsies. In our study, the positive cases for perineural invasion were seen in moderately differentiated OSCC. In the study by Varsha et al., perineural invasion was seen in 41.4% of well-differentiated SCC and 48.10% of moderately differentiated SCC. They also reported that every surgical specimen of OSCC should be evaluated for perineural invasion as it has a significant prognostic value.[3]
Figure 3: Perineural invasion by tumor cells (H and E stain, ×20; ×10 [inset])

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Vascular invasion

“Presence of aggregates of tumor cells within endothelial lined channels or invasion of the media of a vessel with ulceration of the intima” characterizes the lymphovascular invasion.[13] In the present study, we did not find vascular invasion in any of the cases. It has been reported in literature that vascular invasion is considered difficult to define and recognize with certainty.[13] Adel et al. reported lymphatic and vascular invasion in 5% and 3% of OSCC cases, respectively, and found a significant correlation with pathological differentiation.[15] Cavalcante et al. reported vascular invasion in 17.2% of OSCCs.[16] Kurtz et al. in their study on OSCCs found that, on reviewing pathological reports, vascular invasion was reported in 30% of the cases. However, when slides were again reviewed and immunohistochemical analysis was done, vascular invasion was found in 35% and 42% of the cases, respectively.[14] Jardim et al. in their study on SCCs of tongue and floor of mouth found lymphovascular invasion in 40.8% of cases and found a significant correlation with histological grading.[13] Jones et al. reported that lymphovascular invasion has been a good prognostic indicator as it is associated with low survival rate and increased risk of recurrence.[17] However, Adel et al. reported that both lymphatic and vascular invasion did not affect the risk of locoregional recurrence and distant metastasis in OSCC after treatment. Furthermore, in the survival analyses, they found that both lymphatic and vascular invasion are not independent prognostic indicators.[15]

Clear cell change

Clear cell is defined as “a cell, especially a neoplastic, finely vacuolated with central dark nuclei, containing abundant glycogen or other material that is not stained by hematoxylin or eosin, so that the cytoplasm appears clear histologically.”[18] Literature reported that Kuo in 1980 first described the clear cell variant of SCC of skin with extensive hydropic change.[18],[19] The clear cell variant of SCC is characterized by the presence of sheets or islands of clear cells with empty appearing or bubbled cytoplasm.[20] Previously published literature reported that Kuo suggested clear cell change to be a degenerative phenomenon as no evidence of lipid, glycogen, or mucin was appreciated in any of their cases.[19],[20] Apart from hydropic degeneration, other reasons for the clear appearance of cells include processing artifact, improper cellular preservation, accumulation of water, tonofilaments, glycogen, immature zymogen granules, mucin, mucopolysaccharides, lipid, or presence of phagocytized foreign body material in the cytoplasm of tumor cells or paucity of intracellular organelles.[19],[21] “Focal clear cell change in a tumor may become more extensive with tumor progression or it may appear secondarily, reflecting clonal evolution in that tumor.”[21] It is reported in literature that clear cells because of glycogen accumulation predict an unfavorable prognosis as accumulated glycogen in tumor cells renders them resistant to cancer treatment, whereas clear cells associated with degenerative phenomenon are associated with a favorable prognosis.[4],[19] We found clear cells in 13% of cases in our study [Figure 4]a, whereas Frazier et al.[22] found only one case of clear cell variant out of 2340 cases of SCC. Many other researchers did not find any case with clear cells in their series.[22] This may be attributed to the fact that, in our study, we have considered focal clear cell change as positive. We found a significant relation between clear cell change and histological grading of OSCC.
Figure 4: (a) Clear cell change in tumor islands (H and E stain, ×4; ×10 [inset]); (b) tissue eosinophilia (H and E stain, ×40; ×20 [inset]

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Tissue eosinophilia

Tumor-associated tissue eosinophilia was first described by Przewoski in 1896 in cervical carcinoma. It is characterized by the stromal infiltration of tumor by eosinophils, which are not associated with tumor necrosis or ulceration.[23] This infiltration by eosinophils in carcinoma could be attributed to the presence of tumor-derived eosinophil chemotactic factor.[24] The role of eosinophils in OSCC still remains a mystery for researchers. Numerous studies showed that it has a protective role against epithelial neoplastic cells, indicating a favorable prognosis; some studies stated that it has no effect on tumor progression, whereas other studies correlate it with tumor invasion because of the activation of enzyme gelatinase which was widely expressed by eosinophils.[23],[24] In our study, we found tissue eosinophilia in 12 cases of OSCC [Figure 4]b. It has been reported in literature that presence of tissue eosinophils in head-and-neck SCC ranges from 22% to 89%.[23] Although we could not find any significant relation between the histological grade of OSCC and tissue eosinophilia, 10 out of 12 positive cases were of well-differentiated SCC, suggesting that it may be associated with better prognosis. Majumdar et al. in their study found a significant relation between eosinophil count (at the invasive front of the tumor) and histological grade of OSCC as well as pattern of invasion. They also reported a progressive decrease in eosinophil count with increase in the grading of pattern of invasion, suggesting its role in defense against tumor progression.[23] However, Tostes Oliveira et al. reported that there was “no difference in the 5-year and 10-year overall survival and disease-free survival rates between the OSCC patients with absent/mild and intense eosinophilia.”[25]

Giant cell formation

Although giant cell formation in OSCC has been reported in literature, the exact role of multinucleated giant cells in OSCC is not known. Some authors were of the opinion that they are result of immune response by host toward a tumor, but other researchers stated them to have a neoplastic and inflammatory nature.[26]

Foreign body giant cells in SCC were first reported by Cullen in 1900 in cervical carcinoma.[27] Foreign body such as keratin has the ability of inducing chronic granulomatous reaction and is resorbed by the multinucleated giant cells.[26] Thus, foreign body giant cells in SCC are reported to be present near the devitalized and keratinized tumor tissue and have a resorptive function. These giant cells are believed to form either by fusion of mononuclear cells or amitotic division of mononuclear cells. The role of foreign body giant cells on the prognosis of OSCC is still a controversial subject as their formation in SCC was considered a defensive mechanism against spilled keratin into the stroma, whereas posttherapeutic increased keratogenesis may be assumed as an attempt of tumor cells to survive under adverse conditions.[27] Foreign body reaction to keratin by giant cells after chemotherapy or radiotherapy may represent a histological regression of metastatic SCC[26] [Figure 5]a.
Figure 5: (a) Foreign body giant cells (H and E stain, ×4) and (b) tumor giant cells (H and E stain, ×10)

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Different mechanisms were proposed for explaining the formation of malignant tumor giant cells. Tumor giant cells can be formed by cells arrested at G1/G0 or G2/M phase. As energy is required by them to again enter into the cell cycle, they start collecting energy substrate, ultimately resulting in the enlargement of their size. Another common mechanism known for the formation of giant cells is fusion of smaller cells. According to this mechanism, under the influence of aberrant divisions, mitotic cells in G2- or S-phases of cell cycle fuse with each other to form a single bi-nucleated cell. Later on, continuous fusion or divisions in these fused cells result in the formation of multinucleated giant cells. To determine the effect of therapy, it is imperative to keep in mind that giant cells can either get away from cell death or new small-sized cells can arise from them. Increased resistance of giant cells to chemotherapy can be explained by two pathways. In the first pathway, new cells with drug resistance could arise from the arrested giant cells as chemotherapy and radiotherapy affect only the cycling cells. In the second pathway, giant cells re-invade the cell cycle causing multinucleation and polyploidization. The number of giant cell increases, and they can survive in such a state during further treatments, producing new cells or even reverting to the parental cell type[28] [Figure 5]b.

Tertiary lymphoid follicle formation

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid organizations that develop after birth in nonlymphoid tissues, when infiltrating immune cells at the site of chronic inflammation organize themselves both anatomically and functionally, similar to secondary lymphoid organs. They are formed by the aggregation of B-cells in the meshwork of follicular dendritic cells surrounded by T-cells and high endothelial venules.[29],[30] Wirsing et al. in their study found TLS in 21% cases of OSCC in the “peri-tumoral stroma within 0.5-mm distance from the tumor front, in lymphocyte-rich subepithelial areas.”[30] In our study, TLS was observed in 3% cases of OSCC [Figure 1]b, and this difference can be explained on the fact that Wirsing et al.[30] have assessed multiple sections along with the application of immunohistochemical markers. In the present study, all the positive cases for TLS were seen in well-differentiated OSCC, which is in association with the findings of Wirsing et al.[30] where they found majority of positive cases in well-differentiated OSCC. It is found in literature that increased densities of TLS formation correlate with a good prognosis in OSCC, colorectal cancer, liver metastasis, gastric cancer, and non-small cell lung cancer.[29],[30]

 > Conclusion Top

Prognosis and treatment for OSCC is completely governed by histological and morphological grading systems. Addition of criteria into which these unusual features are considered might contribute to more targeted treatment therapy or clearly define its prognosis. In our study, the incidence of unusual features in OSCC was 7.8%. For establishing these unusual features as prognostic factors, a more extensive study on larger number of cases involving special markers is required.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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