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Year : 2020  |  Volume : 8  |  Issue : 1  |  Page : 31-34

Histopathology of oral submucous fibrosis in third dimension with an additional note on hypothesis of epithelial atrophy

Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. Patil Deemed to be University, School of Dentistry, Nerul, Navi Mumbai, Maharashtra, India

Date of Submission24-Apr-2019
Date of Decision01-Aug-2019
Date of Acceptance09-Sep-2019
Date of Web Publication29-Nov-2019

Correspondence Address:
Dr. Sandhya Tamgadge
Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. Patil Deemed to be University, School of Dentistry, Nerul, Navi Mumbai - 400 706, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JMAU.JMAU_23_19

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Oral submucous fibrosis (OSMF) is a potentially malignant disorder, characterized by progressive fibrosis of the lamina propria and underlying connective tissue. It has high chances of malignant transformation. It is caused by betel nut which is very common habit among Indians. Thus, regular monitoring of histopathological changes is mandatory by physicians, private practitioners, and oral pathologists. Therefore, histopathological changes should be understood by everyone who is into health care. This article is a preliminary report on three-dimensional (3D) images and 3D-animation video of histopathological aspect of OSMF designed by author herself, for better understanding of histopathological aspect, which has never been reported so far. Additional hypothesis on epithelial atrophy have also been proposed.

Keywords: Animation, epithelial atrophy, histopathology three-dimensional, hypothesis, images, oral submucous fibrosis, video

How to cite this article:
Tamgadge S, Tamgadge A. Histopathology of oral submucous fibrosis in third dimension with an additional note on hypothesis of epithelial atrophy. J Microsc Ultrastruct 2020;8:31-4

How to cite this URL:
Tamgadge S, Tamgadge A. Histopathology of oral submucous fibrosis in third dimension with an additional note on hypothesis of epithelial atrophy. J Microsc Ultrastruct [serial online] 2020 [cited 2020 Nov 27];8:31-4. Available from: https://www.jmau.org/text.asp?2020/8/1/31/271972

  Introduction Top

Oral submucous fibrosis (OSMF) is a chronic, debilitating disease, characterized by the inflammation and progressive fibrosis of the submucosal tissues (lamina propria and deeper connective tissues). It results in marked rigidity and an eventual inability to open the mouth. The condition is well recognized for its malignant potential and is particularly associated with areca nut chewing.[1] The pathogenesis of OSMF is not well established and hence is believed to be multifactorial. The cascade begins with a juxta-epithelial inflammatory reaction in the oral mucosa, interspersed with healing and fibrosis, with trismus being the end result. It is generally agreed that the pathological alteration in OSMF begins in the lamina propria, and the epithelium responds only secondarily to it.[2]

Researchers have been trying to find out a complete cure. Hence, it is crucial to know the histopathological process by everyone whoever deals with such patients. Therefore, preliminary three-dimensional (3D) images and 3D-animation video of histopathological aspect of OSMF have been designed to make all researchers, students, and practitioners to understand the basic etiopathogenesis, as such work have not been reported so far [Video 1].

  Histopathology Top

Subepithelial changes

It shows two major changes: (1) fibrosis of the lamina propria and (2) muscle changes [Flowchart 1].

Fibrosis of the lamina propria

As per literature, the pathomechanisms underlying the development of fibrosis have been partially elucidated[3] [Figure 1], [Figure 2], [Figure 3].
Figure 1: Three-dimensional image shows fibrosis of subepithelial tissue

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Figure 2: Three-dimensional image shows dense accumulation of collagen fibers and inflammatory cells

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Figure 3: Three-dimensional image shows inner view of stroma

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The role of inflammation in the development of OSMF is similar to the healing response. Therefore, the inhibition of the inflammatory response in injured tissues is considered as a promising strategy to limit the development of fibrosis.[4]

The barrier function of superficial layers of the oral epithelium has been confirmed by experiments that demonstrate an increase in permeability when the surface layers are removed by stripping leads to the formation of major pathways for large molecules, across stratified epithelium, through the intercellular spaces.[4]

Meyer et al. also highlighted the strong association between barrier function impairment, inflammation, and dermal fibrosis.[5] Similarly, in OSMF, microtrauma resulting from continuous areca nut chewing leads to loss of integrity of the epithelium which allows the penetration of toxic molecules through intercellular spaces into the connective tissue (CT) stroma and evokes an inflammatory response. This further results in fibrosis as a part of the healing phenomenon. Defective intercellular junctions lead to fibrosis as a part of healing process has also been mentioned by Krieg et al.[6]

Muscle changes

N. G. EI.-Ladhan mentioned that in OSMF, the degenerative process not only involves the muscle fibers but also its surrounding connective tissue. This was characterized by scanty collagen fibrils and the accumulation of edematous-like fluid around these muscles. If this is the case, then restricted mouth opening would appear to depend not only on subepithelial fibrosis but also on the extent of muscle damage, due to edema and fibrosis.[3],[7],[8],[9]

Trismus in OSMF may be related to loss of a variety of extracellular matrix (ECM) molecules including elastin and replacement of muscle fibers by homogeneous collagen Type I.[9]

Epithelial changes

[Figure 4] and [Figure 5] shows normal epithelium and atrophic epithelium in third dimension.
Figure 4: Three-dimensional image shows normal epithelium, keratin on the surface, and collagen fibers and blood vessels with white blood cells in the stroma

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Figure 5: Three-dimensional image shows histopathology of oral submucous fibrosis showing epithelial atrophy with dense fibrosis

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The basic etiology for epithelial atrophy has been suggested by many researchers is still not clear and still considered as assumptions and hypothesis.[3]

Various explanations have been proposed by various researchers, as follows:

  1. It is the aftermath of heavy fibrosis in the underlying connective tissue.
  2. It is a result of malnutrition.
  3. Few hold the view that the epithelium has become stretched.
  4. It is thinned by the changes in the underlying connective tissue.

Epithelial hyperplasia could be an adaptive response to local irritants to provide a greater degree of protection to the underlying tissues. The hyperplastic epithelial response and later atrophy probably reduce the barrier function of the mucosa to local irritants.[10]

There could be one more hypothesis based on four research evidences collectively, as follows:

First evidence – Effect of masticatory forces on the width of the oral epithelium

It is suggested that the length of rete ridges is positively correlated with the strength of mechanical stresses on the mucosa.[11],[12] Hence, masticatory mucosa usually has longer rete ridge than lining mucosa, as amount of physical forces are directly proportional to the length of rete ridges.

Wu et al. stated that rete pegs are well developed in dentulous patients as compared to edentulous, as seen in old age, where the muscle forces are decreased, and less force is transmitted to rete pegs which leads to atrophy of the epithelium.[11],[12]

Second evidence – Effect of stroma on overlying epithelium

Recent studies also showed that stromal cells and their matrices can influence the upper epidermis development; therefore, oral epithelium too structurally depends on underlying lamina propria.[11]

Third evidence – Lamina densa, anchoring fibrils, and lamina propria, a unit

In the oral mucosa, some juxta epithelial collagen fibrils of the lamina propria curved toward the epithelial cells and passed through the anchoring fibril network and apparently merged with the basal surface of the lamina densa. Thus, Adachi and Hayashi stated that there is a direct connection of juxta epithelial collagen fibrils with lamina densa which could be a ubiquitous anchoring system to stabilize the epithelial tissues.[13]

Adachi et al. also proposed that collagen V might also be involved in anchoring of epithelia to underlying connective tissues.[14] Thus, tension in underlying connective tissue will have a direct effect on rete pegs through the lamina densa.

Fourth evidence – Facial muscle force is directly transmitted to the oral epithelium

The potential of force transmission between skeletal muscles through inter- and extra-muscular connective tissues has been demonstrated. Investigators have definitively shown that epimuscular pathways can transmit substantial force. Thus, it could also be hypothesized that orofacial muscle forces are transmitted to adjacent CT stroma and reach directly to the oral epithelium through anchoring fibrils, as cheek and lip muscles do not have bony insertions.[15] Thus, when muscle undergoes complete fibrosis, in OSMF, the muscle force does not reach the oral epithelium due to fibrous connective tissue present in between muscles and overlying epithelium, leads to disuse atrophy.

Nevertheless, this hypothesis cannot be applied to fibrosis of the hard palate as it does not have muscles but still undergoes fibrosis. Here, the epithelial atrophy could be related to microtrauma due to continuous chewing of the areca nut which leads to inflammation and fibrosis similar to the healing process as suggested by Huub Maas et al.[15]

Cheek and lip muscles do not have bony insertions and tendons; therefore, the force of contraction will get transmitted to the oral epithelium through the connective tissue and anchoring fibrils, as all these tissues are connected as unit as mentioned earlier. Chi Zhang stated that two pathways are involved in transmitting force from muscle fibers to tendon: (1) longitudinal transmission, i.e., transmission along the muscle fibers through the myotendinous junctions to the tendon and (2) lateral transmission, i.e., transmission laterally across one muscle fiber to the adjacent connective tissue network, the ECM, and finally to the tendon.[16] However, cheek and lip muscles do not have bony insertions; therefore, the force gets transmitted to the surrounding connective tissue.[16]

  Conclusion Top

Thus, it can be finally be hypothesized that when severe fibrosis takes places in the lamina propria and underlying muscles, the muscle functions are limited. Therefore, the contractile force does not reach the epithelium through the fibrosed lamina propria and anchoring fibrils. Due to which rete pegs do not get stretched by muscle pull and epithelium undergo disuse atrophy.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Shafer WG, Hine MK, Levy BM. Potentially malignant disorders. Shafer's Textbook of Oral Pathology. 5th ed. India: Elsevier; 2006. p. 358-61.  Back to cited text no. 1
Neville DW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology. 3rd ed. Philadelphia: W.B. Saunders; 2009. p. 5289.  Back to cited text no. 2
Rajendran R. Oral submucous fibrosis: Etiology, pathogenesis, and future research. Bull World Health Organ 1994;72:985-96.  Back to cited text no. 3
Squier CA, Kremer MJ. Biology of oral mucosa and esophagus.J Natl Cancer Inst Monogr 2001;29:7-15.  Back to cited text no. 4
Meyer M, Müller AK, Yang J, Ŝulcová J, Werner S. The role of chronic inflammation in cutaneous fibrosis: Fibroblast growth factor receptor deficiency in keratinocytes as an example. J Investig Dermatol Symp Proc 2011;15:48-52.  Back to cited text no. 5
Krieg T, Abraham D, Lafyatis R. Fibrosis in connective tissue disease: The role of the myofibroblast and fibroblast-epithelial cell interactions. Arthritis Res Ther 2007;9 Suppl 2:S4.  Back to cited text no. 6
El-Labban NG, Canniff JP. Ultrastructural findings of muscle degeneration in oral submucous fibrosis. J Oral Pathol 1985;14:709-17.  Back to cited text no. 7
Sannad A, Tamgadge S, Tamgadge A, Yadav KS, Giri A, Wankhede M, et al. Total serum protein estimation and its correlation with clinical and histopathological grading using masson's trichrome stain in patients of oral submucous fibrosis. Contemp Clin Dent 2017;8:286-92.  Back to cited text no. 8
[PUBMED]  [Full text]  
Ekanayaka RP, Tilakaratne WM. Oral submucous fibrosis: Review on mechanisms of pathogenesis and malignant transformation. J Carcinog Mutagen 2013;S5:002. [Doi: 10.4172/2157-2518.S5-002].  Back to cited text no. 9
Isaac U, Issac JS, Ahmed Khoso N. Histopathologic features of oral submucous fibrosis: A study of 35 biopsy specimens. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:556-60.  Back to cited text no. 10
Wu T, Xiong X, Zhang W, Zou H, Xie H, He S, et al. Morphogenesis of rete ridges in human oral mucosa: A pioneering morphological and immunohistochemical study. Cells Tissues Organs 2013;197:239-48.  Back to cited text no. 11
Ciano J, Beatty BL. Regional quantitative histological variations in human oral mucosa. Anat Rec (Hoboken) 2015;298:562-78.  Back to cited text no. 12
Adachi E, Hayashi T. Anchoring of epithelia to underlying connective tissue: Evidence of frayed ends of collagen fibrils directly merging with meshwork of lamina densa. J Electron Microsc (Tokyo) 1994;43:264-71.  Back to cited text no. 13
Adachi E, Hopkinson I, Hayashi T. Basement-membrane stromal relationships: Interactions between collagen fibrils and the lamina densa. Int Rev Cytol 1997;173:73-156.  Back to cited text no. 14
Maas H, Sandercock TG. Force transmission between synergistic skeletal muscles through connective tissue linkages. J Biomed Biotechnol 2010;2010:575672.  Back to cited text no. 15
Lawlor KT, Kaur P. Dermal contributions to human interfollicular epidermal architecture and self-renewal. Int J Mol Sci 2015;16:28098-107.  Back to cited text no. 16


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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