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147]

Review Article

A comprehensive review of surgical

margin in oral squamous cell carcinoma Mamata Kamat,
Bhagawan Das

highlighting the significance of tumor‑free

Rai1,
Rudrayya S.
Puranik2,
surgical margins Uma Vasant
Datar3

PhD Scholar, Faculty

ABSTRACT of Dental Sciences,
Pacific Academy of
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity, and surgery is the most accepted line Higher Education and
of treatment. The surgical margins (SMs) or resection margins are boundaries of resection specimen excised by the surgeon. The Research University,
status of these resected SMs is an important and valuable tool to predict the treatment outcome. It is necessary to attain optimal 1
Department of Oral
SM to avoid local recurrence and improve overall survival. However, the controversies exist regarding the concept of optimal SM. and Maxillofacial
There are various factors that influence the assessment of the SMs. In addition, apart from routine histopathology, the molecular Surgery, Pacific Dental
College and Hospital,
assessment of resected margins has recently gained value which has a promising role for margin surveillance. Furthermore, the Udaipur, Rajasthan,
histological and molecular appraisal of tumor‑free margins is also necessary to standardize the treatment modalities. Hence, this 2
Department of
review aims to summarize the above issues that influence the evaluation of SMs of OSCC along with recent updates. Furthermore, Oral Pathology
an attempt has been made to give an overview about future possible approaches for the tumor‑free margins. An electronic search and Microbiology,
was performed for items related to the evaluation of SMs in OSCC, and the obtained articles were critically assessed and the relevant P.M.N.M. Dental
College and Hospital,
information was extracted and summarized. Bagalkot, Karnataka,
3
Department of
Oral Pathology and
KEY WORDS: Oral squamous cell carcinoma, surgical margins, tumor‑free margins Microbiology, Bharati
Vidyapeeth (Deemed
to be University)
Dental College and
INTRODUCTION of the current approaches of SM evaluation in Hospital, Sangli,
OSCC and emphasize the call for inclusion of Maharashtra, India
Oral squamous cell carcinoma (OSCC) is the “molecular status” of tumor‑free margins.
For correspondence:
sixth to eight most common cancer around
Dr. Mamata Kamat,
the world. [1] Surgical resection is the primary Literature search of the PubMed/Medline database QRTS No 7,
mode of management of OSCC followed by was performed using the following keywords B Block, Bharati
adjuvant radiotherapy and chemotherapy or search terms: Oral, squamous cell carcinoma, Vidyapeeth Medical
Campus, Miraj
when needed. [2] In spite of advances in surgical margins, negative resection margins, Road, Wanlesswadi,
diagnostic and treatment modalities, the 5‑year recurrence, and prognosis. Citation pearl growing Sangli - 416 416,
survival rates are low at <50%. [1,3] The low technique was employed, and reference articles of Maharashtra, India.
survival rate is attributable to locoregional the selected article were referred. After exclusion E‑mail: kmamata@
yahoo.com
recurrence and lymph node metastasis. The of the unrelated topics, articles in other than
evidence of tumor in or close to surgical English language, and case reports, 38 full‑text
margin (SM) indicates likelihood of local articles (including narrative reviews, n = 09;
relapse after resection. [3,4] Hence, histological systematic reviews, n = 03; and original studies,
evaluation of SM is of prognostic significance. n = 26) were included in this review.
However, tumors with histologically negative Access this article online
margins (HNMs) are also known to demonstrate This is an open access journal, and articles are distributed under the terms of the Website: www.cancerjournal.net
locoregional recurrence, [3] which mandates the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which DOI: 10.4103/jcrt.JCRT_273_17
allows others to remix, tweak, and build upon the work non-commercially, as
molecular analysis of SM to identify the residual long as appropriate credit is given and the new creations are licensed under the Quick Response Code:

cancer cells and to recognize genetically identical terms.

altered fields. Herein, we present an overview For reprints contact: reprints@medknow.com

Cite this article as: Kamat M, Rai BD, Puranik RS, Datar UV. A comprehensive review of surgical margin in oral squamous
cell carcinoma highlighting the significance of tumor-free surgical margins. J Can Res Ther 2019;15:449-54.

© 2018 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow 449
[Downloaded free from http://www.cancerjournal.net on Thursday, February 18, 2021, IP: 37.251.223.147]
Kamat, et al.: Surgical margin and OSCC
DISCUSSION
Types of tumor margin
Broadly, the margins of tumor have been categorized as:
• Clinical margins: They are margins of tumor on clinical
observation and palpation, which are included during
resection of tumor tissue[5]
• SMs: SM/resection margin refers to any tissue plane
where the surgeon’s knife meets the patient.[6] Along
with the surface mucosa (at the edge of the tumor),
it also include the submucosal and deeper connective
tissues all around tumor.[7] SMs reflect the surgeons
endeavor to excise all the tumor tissue along with
preservation of adjacent unaffected tissue, thus
balancing the oncological and functional goals. [8]
Microscopically, SM can be further categorized into
histological and molecular margins.
a. Histological margins: The pathologists screen the
edges/margins of resection specimen for evidence
of tumor cells. The UK Royal College of Pathologists’
guidelines for screening of margins propose that both
the “mucosal” and “deep” (deep margins include
submucosa, skeletal muscle, and bone) margins should
be evaluated. According to approximation of tumor
cells, mucosal and deep margins are subdivided into
clear, close, and involved[9‑11]
• C l e a r / n e g a t i v e m a r g i n : H i s t o l o g i c a l
distance of >5 mm from the invasive carcinoma
to SMs
• Close margin: Histological distance of 1–5  mm
from the invasive carcinoma to SMs
• Involved/positive margin: Histological distance
of <1 mm from the invasive carcinoma to
SMs. On the basis of the following histological
criteria, Looser et al.[3,12] suggested a classification
of positive margins as: (1) margin closeness
(tumor within 0.5 mm), (2) premalignant change in
margin, (3) in situ cancer in margin, and (4) invasive
microscopic cancer in the margin.[3,12]
b. Molecular margins: The histologically normal margins
may harbor genetic changes. Thus, various molecular
markers have been recently employed to detect these
fields of genetically altered cells.[5,13,14]
Assessment of surgical margins
Evaluation of resection margins is an important
part of pathological examination. The status of SMs
(clean/close/positive) has therapeutic and prognostic
implications.[15] Different methods have been devised for
accurate assessment of SMs and subsequently the adequacy of
excision of tumor. Ravi and Annavajjula[16] proposed a working
classification of methods for evaluation of SM according to
time of usage with respect to period of surgery [Table 1].[5] It
is recommended that from the array of available methods,
suitable techniques should be employed by the surgeon and/or
pathologists to ensure clearance of tumor [Figure 1].
450
Table 1: Evaluation of surgical margins
Preoperative Intraoperative Postoperative assessment
assessment assessment
Vital staining Thickness of Mohs microsurgery
Fluorescent resected margins Frozen technique
visualization Frozen section (intraoperative assessment)
analysis Formalin technique
TIC (postoperative assessment)
Microendoscope Ultrasonography
OCT Molecular assessment
Gene signature
TIC=Touch imprint cytology, OCT=Optical coherence tomography
Inking of surgical margins
Accurate anatomical orientation of excised OSCC specimen
and identification of all SMs forms an integral part of
histopathological evaluation. The methods used for identifying
SM before and after processing include use of dye/pigments,
sectioning techniques, applying clips, or sutures with former
being the most reliable.[17] Due to its ease of application and
clear demarcation of the borders, recently, inking of margins
is commonly used. Conventionally, India ink has been used to
mark the surgical resected margins.[18] India ink is a protein
based and hence it securely fixed to the tissue by cross‑linked
fixatives. However, the dye is more prone to wash off.[19] Hence,
multicolor inking is increasingly used (1) to examine multiple
surfaces/margins, (2) for postoperative comparison of tissue
planes, (3) for the benefit of postgrossing three‑dimensional
reconstruction, and (4) to reduce identification error when
multiple sampling is required from the same tissue or when
obtaining similar specimens from different patients.[18]
Although the benefit of colored inks in surgical and
histopathological practice is appreciable, the availability of
these colored inks is limited. Hence, the acrylic colors have
been employed as a substitute for multicolored surgical
ink.[17,20] It has been suggested that acrylic colors are more
suitable as surgical ink than India ink because of its availability
in different colors, ease of application, faster drying time,
no contamination of processing fluids, easy availability, and
excellent visibility in paraffin blocks and under microscope.[17,20]
Factors affecting the assessment of surgical margins
It is often observed that discrepancy exists between the SMs
measured by the surgeon (which seems appropriate before/at
the time of surgery) and the margins analyzed by pathologists
after resection. Various factors have been postulated for this
inconsistency which include
• Tissue shrinkage after resection and pathologic
processing[3,21,22]
• Decrease in the dimension of the tissue under tension on
surgical release from the surrounding tissue.[23]
Tissue shrinkage
Tissue shrinkage is one of the important factors which
cause discrepancy in the measurement of preoperative and
postoperative margins.[3] This tissue shrinkage is dependent
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Kamat, et al.: Surgical margin and OSCC

on various intrinsic and extrinsic factors.[22] Intrinsic factors Table 2: Degree of shrinkage of surgical margins obtained
are difference in tissue composition, tumor site, tumor from different anatomical sites
stage, cohesiveness of tumor cells, degree of keratinization, Authors Sample Site Shrinkage
degree of inflammation, and tumor site. It is also observed (year) size (%)
that shrinkage varies between different margins of a single Mistry et al., 27 Buccal mucosa 21.2
2005[24] Tongue 23.5
specimen from the same location.[21,22] Due to replacement of Cheng 41 Buccal mucosa, mandibular 71.90
muscle by tumor tissue, intratumoral shrinkage is reported to et al., alveolar ridge, retromolar trigone
be less compared to the shrinkage at SMs.[2,21] Tissue fixation 2008[25] Maxillary alveolar ridge and palate 53.33
and tissue processing represent the extrinsic factors. It has Tongue 42.14
El‑Fol et al., 61 Buccal mucosa 66.7
been suggested that the duration of fixation does not affect 2015[26] Tongue 35
the shrinkage rate of SMs.[21] Till date, only three studies[24‑26] Floor of mouth 33.3
have analyzed the degree of shrinkage based on anatomical Retromolar trigone 16.7
location of the tumor and their findings are depicted in Table 2. Mandibular alveolus 15.4
Higher rate of tissue shrinkage is reported for margins which
do not have bony support.[2] In the light of above‑mentioned Table 3: Effect of tumor location on the margin status
findings, shrinkage should be calculated separately for each Site of Margin status Comment
margin. Sarode and Sarode[22] designed a new formula for tumor
shrinkage calculation: Tongue Involved margins are less
This is attributed to
common in this site the anatomy of tongue
A × 10 permitting the design
Percentage of Shrinkage = 100 −
B and adaptation of
hemiglossectomy adequate
Where A is the microscopic distance in µm calculated with for achieving clear margins
the help of image analyzer/oculometer and B is the number Floor of Frequently show involved Poor access and
of basal cells within distance “A.” mouth and margins anatomical constraints
retromolar In case of floor of mouth,
areas existence of loose areolar
Mistry et  al. reported that the mean shrinkage in T1/T2 tissue around, and deep to
tumors is to be significantly more than that in T3/T4. This has the sublingual gland, the
been attributed to tumor‑related destruction of contractile deep localization of muscle
bulk provides room for
elements surrounding cancer. [24] In contrast, Cheng infiltration of tumor and the
et al.[25] observed higher discrepancy in T3/T4 tumors than invasion of lingual nerve
T1/T2 which has been correlated with greater microscopic and sublingual ganglion
invasiveness in late tumors. Both the studies differed in the can be the potential source
of dissemination
anatomical sites of tumor and the number of cases studies Buccal Top‑ranked site for There is natural laxity of
was also limited. Hence, further studies are required to mucosa involved margin a split‑thickness cheek
obtain a more realistic conclusion regarding SM shrinkage resection that leads to
and tumor stage. excess shrinkage of
resected specimen
Bone Involved bone margins are When bone is involved,
Mucosal elasticity rarely encountered and are invasion may be seen at
The mucosal elasticity is thought to influence the tumor usually seen in association the perisoteum overlying
dimension and SMs in case of buccal carcinoma. Recently, Tsai with involved mucosal or the cortical plates or within
deep soft‑tissue margin the cancellous bone[6]
et al.,[23] in their study, found a 32.35% magnification of buccal
mucosa elasticity due to stretching during maximum mouth
opening and thus suggested that this elasticity should be taken suggested to influence the adequacy of margin resection. It
into account while computing adequate SMs for transoral is implicated that in tumors that invade deeply as nests and
resection of buccal mucosa. cords of cells require a wider margin than tumors with broad
and flat‑pushing invasive front.[27]
Optimal resection margin
Optimal SM forms a pivotal role to ensure local control and In view of the above‑mentioned facts, currently, “1‑cm
to decide adjuvant radiotherapy. The adequacy of resection three‑dimensional margin” that reflects into >5 mm of
depends on tumor site, anatomical restrictions, biological pathological margin is highly recommended. Hence, to obtain
characteristics, and extent of surgery.[27,28] overall margin >5 mm, clinical margin for resection should
be >1 cm for mucosal and deep margins and 1 cm for bony
Factors associated with rate of involved margins according to margins.[3]
various anatomical sites are depicted in Table 3.[23] Literature
shows that involved mucosal margins are rare compared to The notion of close margin is a less understood entity and
involved deep margins.[10] The pattern of tumor invasion is also there is a lack of standard definition in the head and neck

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Kamat, et al.: Surgical margin and OSCC

Resection specimen be identified by means of immunohistochemistry (IHC) or

genetic analysis.[30]

Proper orientation (Inking)
Frozen Sections
Histopathological examination
Close margin
Involved margin
Molecular & genetic studies
• Adjuvant radiotherapy
• Targeted Chemotherapy
• Predict local recurrence
& survival rate
Figure 1: Algorithm for evaluation of surgical margins in OSCC
Clear margin
Molecular & genetic
studies
• To identify genetically
altered fields
• To identify patients at
risk for local recurrence
• To re-evaluate the
treatment alternatives
• For closer disease
monitoring
Determining the “molecular status” of the SMs is one of
the newer diagnostic methods employed in OSCC. As the
genetic alterations pave the way for the phenotypic changes
of the epithelium, there is a need for molecular assessment
of HNMs.[31] However, molecular studies of HNMs in OSCC
are sparse. Recently, molecular strategies such as IHC
expression of markers and gene amplification of Loss of
Heterozygosity (LOH) of markers by the use of polymerase
chain reaction have been studied, and results suggest that
they provide useful prognostic information and influence
the clinical management.[14,32‑38] Studies have shown that
subjecting the SMs for molecular analysis helps to determine
the adequacy of tumor tissue removal. [5] Overexpression
of tumor suppression genes (such as p53 and TP53),[32,34,36]
oncogenes (such as epidermal growth factor receptor),[35] and
proto‑oncogenes (like Her‑2)[38] in margins reported to be cancer
free on routine histopathological examination explains the
initiation of premalignant and malignant changes at theses
margins, which may further result in recurrence and second
primary tumors.[31] The summary of the molecular studies on
HNMs in OSCC has been depicted in Table 4.

region.[28] As the lymphatic drainage, vascularization, and the
presence of biologic barriers (cartilage, bone, and fascia) vary
among different sites of the oral cavity, the unique definition
of “close” for every site may not be practically applicable.[28]
Hence, the traditional definition of 5 mm as close needs to be
re‑evaluated.[3]
While deciding the optimal SM, one should take into account
the various aforementioned parameters and individualized
accordingly to the patient. Furthermore, the preferred optimal
SM should assist in achieving adequate local control and avoid
inadequate resection or unnecessary functional morbidity from
too much resection.
Histologically tumor‑free surgical margins
As the entire oral mucosa is exposed to carcinogens, changes
occur at histological and molecular level even at the clinically
normal margins of tumor. On routine histopathology,
tumor‑free margins may show signs of chronic mucosal
irritation, cellular atypia, and mild epithelial dysplasia and
thus reported as HNMs.[29]
Molecular margins
Literature reports that about 10%–30% of OSCC patients
with HNMs report local recurrence. The suggested reasons
include (a) residual cancer cells undetected by routine
histopathology (minimal residual cancer) and (b) nonresected
“field of genetically altered cells” that remain macroscopically
undetectable. These fields serve as fertile grounds for
the evolution of potentially malignant lesions as well as
invasive cancer.[4,30] Majority of these altered fields can only
Hence, it seems logical to subject SMs to molecular analysis
to predict the prognosis and recurrence so as to improve the
quality of life for OSCC patients. However, further studies
are required to address the need for assessment of molecular
markers from research stance.
SUMMARY AND CONCLUSION
Assessment of SMs in OSCC forms an integral part to predict
the treatment outcome. Factors such as tumor site, tumor stage,
tissue shrinkage, and mucosal elasticity should be taken into
consideration while deciding the optimal resection margin.
Currently, a 1‑cm three‑dimensional margin is considered
optimal. Patients with positive and close margins should be dealt
with caution as they have elevated risk for local recurrence. The
close resection margins should be considered separately with
regard to prognosis. With availability of numerous techniques,
the best suitable method or multimodal diagnostic protocol has
to be followed by the surgeons to achieve complete clearance
of SMs to improve the morbidity of the patients. The presence
of genetic alterations in HNMs demands the refinement of
definition of tumor‑free margins in OSCC and it is recommended
to include molecular status along with histology. This would
influence the therapeutic approach and predict local recurrence
and survival rate. Beholding the role of theses genetic and
molecular alterations to predict recurrence and survival,
further studies are recommended that focus on validation and
assessment of clinical utility of these molecular markers.
Financial support and sponsorship
Nil.

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Kamat, et al.: Surgical margin and OSCC

Table 4: Summary of studies on tumor‑free surgical margins of oral cancer

Author Marker and Results Remark
technique
Van Houten VM TP53‑mutated DNA by 66% showed TP 53‑mutated DNA +ve margins Absence of p53‑mutated DNA is
et al., 2004[30] phage plaque assay and 9 of them developed regional recurrence significantly associated with lack of
and mutated p53 40/50 samples showed mutated p53 protein recurrence
protein by IHC (n=76) overexpression
Bilde et al., P53, p16, Chk2, p53: Expression in 12/16 margins Small group of cells expressing p53 and
2009[32] laminin‑5, and p16: Expression in 11/16 margins p16 in histologically normal margins
glycosylated oncofetal Chk2: 1/16 represents early malignant changes
fibronectin by Laminin‑5: Glycosylated oncofetal fibronectin
IHC (n=16)
Reis et al., MMP‑1, COL4A1, 138 overexpressed genes in OSCC Overexpression of 4‑gene
2011[13] P4HA2, and THBS2 4 genes were identified that showed prognostic signature (MMP‑1, COL4A1, P4HA2,
gene signature by value and THBS2) in HNMs was significantly
PCR (n=199) associated with recurrence
Vosoughhosseini EGFR by IHC (n=40) 10% of HNMs were stained with EGFR Detection of EGFR in HNMs may identify
et al., 2012[35] patients at risk for tumor recurrence and
can benefit from anti‑EGFR treatments
de Carvalho Expression levels 36.4% of HNMs harbored overexpression of MMP‑9, EPCAM, and PTHLH are frequently
et al., 2012[31] of 5 genes, PTHLH, at least 1 of the 3 selected genes (MMP9, and specifically overexpressed in HNM of
EPCAM, MMP9, EPCAM, and PTHLH) HNSCC
LGLAS1, and 23.6%: Overexpressed MMP‑9 Overexpression of PTHLH and MMP‑9 in
MET by qRT‑PCR 10.9%: Overexpressed EPCAM HNMs significantly correlated local failure
assays (n=55) 9.1%: Overexpressed PTHLH and development of SPT
Mohtasham E‑cadherin and Among the surgical margins E‑cadherin and MMP‑9 expression at
et al., 2014[33] MMP‑9 by IHC (n=58) 82.1% of advanced stage and 84.2% of early HNMs have prognostic values in OSCC
stage overexpressed E‑cadherin patients with E‑cadherin being the preferred
MMP‑9 showed higher immunoreactivity in predictor
advanced stage
Subramani OPN by IHC (n=20 95% of tumor tissues and 55% of HNM samples Elevated levels of OPN in HNMs of OSCC
et al., 2015[37] NOM, 20 OSCC, 20 showed elevated OPN expression may predict risk of recurrence
tumor‑free margins)
Singh et al., p53 and eIF4E by 3/7 patients with recurrence had p53‑positive Expression of eIF4E marker appeared to be
2016[34] IHC (n=24) margins a more marked prognosticator compared
6/7 patients with recurrence had eIF4E‑ positive with p53
margins
Jelovac et al., c‑erb‑B2, c‑myc, and Amplification of Patients with c‑erb‑B2 amplification in
2016[38] H‑ras gene alterations c‑erb‑B2 in 22% HNMs may benefit from targeted c‑erb‑B2
in tumor‑free c‑myc in 30% and inhibitors
margins of OSCC by H‑ras in 12%
RT‑PCR (n=50) Patients with c‑erb‑B2 amplification in HNM had
lower 5‑year survival rates and high probability
of recurrence than patients without
Wang et al., LOH of markers on 23/71 show genetic alterations in their HNM P16 and D9s1747 or p53 and TP 53 when
2016[36] 9p21 and 17p13 10/23 with genetic alterations developed a LR combined, the predictive value is more
(TP 53) by PCR and 5/45 without genetic alterations in their HNM sensitive
IHC of p53, p14, p15, developed a LR P53 + tp53 has the best accuracy and PPV
and p16 (n=71 HNM) for predicting LR
HNM=Histologically negative margins, IHC=Immunohistochemistry, MMP‑1=Matrix metalloproteinase 1, MMP‑9=Matrix metalloproteinase‑9, OSCC=Oral
squamous cell carcinoma, EGFR=Epidermal growth factor receptor; qRT‑PCR=Quantitative reverse transcriptase‑polymerase chain reaction, PTHLH=Parathyroid
hormone‑like hormone, SPT=Second primary tumor, PPV=Positive predictive values, LR=Likelihood ratio, OPN=Osteopontin

Conflicts of interest margins in oral cancers: Implication of close margin status in

There are no conflicts of interest.
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