Surgical Management of Oral Squamous Cell Carcinoma

Fig. 6.1

Schematic representation of surgical margin, based on the method used to interpret the margins. Surgical margins need to be assessed at mucosal and soft tissue level
Filed Cancerization
The biologic basis of field cancerization is described in detail in Chap. 1. Oral cancer develops as a multistep, multifocal process. Slaughter et al. [4] suggested the hypothesis of field cancerization based on their observation that serial sectioning of histologic examination of normal appearing mucosa revealed preneoplastic clones of cells away from the primary tumor. These lesions arising in a preconditioned epithelium can progress into new cancer. Based on the spatial and temporal relationship as well as the genetic similarity, Braakhuis et al. [40] proposed three distinct types of local tumor relapse: local recurrence, second primary tumor, and second field tumors (Fig. 6.2). Tumors that are developed less than 2 cm away from the primary tumor and in less than 3 years are considered as local recurrence. If they are genetically identical, it can be considered as true local recurrence. If they are genetically related, it is considered as second field tumors. Those tumors that arise more than 2 cm away or over 3 years after the first tumor, it can be considered as second primary tumor. Based on the genetic similarity to the initial tumor, it can be considered as second field tumor if the tumor is genetically related or as true second primary tumor if they are genetically distinct. The genetic identity of the tumor in this study was carried out by analyzing the pattern of loss of heterozygosity at position 3p12, 3p14, 3p21, 3p24.3, 9p21, 17p11-12, and 17p13.1 [3]. It has been observed that these genetic changes can occur 5–7 cm away from the primary tumor.

Fig. 6.2

Spatial, temporal, and genetic relationship of local disease relapse. LR local recurrence, SFT second field tumor, SPT second primary tumor (Adapted from Braakhuis et al. [40]
Several molecular markers have been employed to identify conditioned mucosa. This includes p53 [6], eIF4E [7], methylation-specific polymerase chain reaction for promoter hypermethylation of O-6-methylguanine-DNA-methyltransferase (MGMT) gene, a DNA repair gene [5]. The clinical application of this technique is limited by the fact that these assays have high false-positive rates as well as it takes over 5 h to process the sample, limiting its intraoperative usage. It was also observed that adjuvant postoperative radiation therapy did not improve recurrence rate in subjects with molecular margin positive tumors [8].
Pattern of Invasion
It has been reported that deep positive margin carried a worse prognosis compared to mucosal positive margin. Pattern of invasion of tumor is considered as the primary determinant of probability of deep margin positivity. Brandwein-Gensler et al. [41] studied this relationship in a series of 168 patients with oral squamous cell carcinoma. They modified the existing pattern of invasion grading into five types: type 1, board tumor front; type 2, fingerlike tumor front; type 3, tumor islands of >15 cells; type 4, tumor islands with <15 cells; and type 5, tumor islands with <15 cells more than 1 mm apart. They have observed higher locoregional failure and overall survival in patients with more infiltrative tumor. They have also reported increased incidence of positive margin, perineural invasion, and low lymphocyte infiltration with more infiltrative tumor. Combining these prognostic factors (pattern of invasion, perineural invasion, and lymphocyte infiltration), the authors identified three risk groups. They have observed that while for high-risk group adjuvant postoperative radiotherapy was beneficial, in low-risk groups even with positive margin, there was no additional benefit with adjuvant radiotherapy. This fact was further confirmed by Ch’ng et al. [7]. In a series of 144 patients with close but uninvolved margin (<5 mm), surgery alone obtained locoregional control rate of 91 % and disease-specific survival rate of 84 %. They have also observed stepwise reduction of the disease-specific surgical rate with each addition of high-risk factors of infiltrative pattern of invasion, perineural invasion, depth of invasion, and tumor subsite (buccal mucosa).
Sindhu et al. [9] further evaluate the factors that determine the pattern of invasion and which confer poor treatment outcome. They have hypothesized that the pattern of invasion of oral cancer is determined by the density of cancer stem cells (CSC); the higher the density of cancer stem cells the worse the pattern of invasion (Fig. 6.3). Furthermore, the CSCs have higher migration capacity as well as are resistant to both radiation and chemotherapy. They have observed a close correlation of pattern of invasion and putative cancer stem cell marker CD44 and poor treatment outcome. The CD44 expression also correlated with perineural invasion as well as lower lymphocyte infiltration.

Fig. 6.3

Correlation of pattern of invasion and cancer stem cells. (a) Pushing boarder, (b) fingerlike boarder, (c) infiltrative boarder. (d) Concept of cancer stem cells defining the pattern of invasion (Sindhu et al. [9]) Clinical Implications

Based on the above findings and randomized clinical trial of adjuvant therapy in head and neck cancer [42], one can formulate an algorithm for adjuvant treatment. This data is summarized in Table 6.1. It is to be noted that level 1 evidence is available only in determining when to give adjuvant chemoradiotherapy. All other recommendations are based on the interpretation of basic science and clinical research data, the art of clinical medicine practice.

Table 6.1

Clinical decision making based on the surgical margin status
Margin Status
Management strategy
>5 mm histologically uninvolved margin, no dysplasia, or molecular markers of field cancerizationb
Standard clinical follow-upc
Good local control rate (91.6 %) and good disease-specific survival (70.5 %)
Nason et al. (2009) [37]
>5 mm histologically uninvolved tissue, evidence dysplasia, or molecular markers of field cancerization in adjacent mucosab
No adjuvant treatment, intense follow-up for early detection of second field cancer or second primary tumor, counseling for habit cessation and enroll in chemoprevention trials
High risk for second field cancer or second primary tumor (80 %) but has good disease-specific survival rate (60 %). Presence of carcinoma in situ has similar local recurrence rate (84 % vs 64 %) and similar poor disease specific survival rate (23 % vs 28 %).
Looser et al. (1978) [19]
Tabore (2001) [3]
>5 mm histologically uninvolved tissue, with additional poor prognostic factorsd
Consider adjuvant radiation
Moderate local disease control rate 74–91 %
Brendwein-Genslet et al. (2005)
<5 to >1 mm histologically uninvolved tissue with no additional poor prognostic factorsd
No adjuvant treatment, standard follow-up
Good local control rate (87–91.4 %) and good disease-specific survival (84 %)
Ch’ng et al. (2013) [9]
Weijers et al. [13]
Brendwein-Genslet et al. (2005)
<5 to >1mm histologically uninvolved tissue with additional poor prognostic factorsd
Adjuvant radiation
Moderate local control rate (86.4 %) and overall survival rate (69.6 %)
Nason et al. (2009) [37]
Ch’ng et al. (2013) [9]
Brendwein-Genslet et al. (2005)
<1 mm histologically uninvolved tissue or cut-through margin
Reresection if technically and clinically feasiblee followed by CT-RT
Low local control rate (20–45 %) and disease-specific survival rate (7–10 %)
Byers (1978) [58]
Chen (1987) [38]
aPrognosis in relation to surgical margin status. All other factors are considered equal
bMolecular markers of field cancerization: LOH markers, eIF4E,p53, p16, CD44
cStandard follow-up regimen: clinical review once every two months during the first year, 3 months during the second year and every six months during years 3 to five, and once a year since then
dPoor prognostic tumor features: infiltrative boarders, perineural invasion, lymphovascular invasion, high CD44 expression, and low lymphocyte reaction at the tumor borders Ch’ng et al. [9], Weijers et al. [13], Brendwein-Genslet et al. (2005)
eAs positive surgical margin is often associated with poor prognostic features and not always due to technical error, CT-RT is recommended even after securing negative margin after reresection

6.2.2 Intraoperative Pathology Consultation (Frozen Section)

Intraoperative pathology consultation (frozen section) is often required for the successful execution of ablative surgery. It is essential for surgeons to know the capabilities and limitations of intraoperative pathologic consultation. The surgeons also should have a good working relationship and effective communication plan with the pathologists.
Common indications for intraoperative consultations are the following:

  1. 1.
    Frozen section of surgical margins to ensure completeness of resection.
  2. 2.
    Intraoperative assessment to plan the extent of surgical procedure (e.g., marginal vs segmental mandibulectomy).
  3. 3.
    Ensure that the diagnostic sample has representative tissue.
  4. 4.
    Evaluation of lymph nodes.
Frozen section of oral squamous cell carcinoma has a diagnostic accuracy rate (correlation of frozen section with that of permanent section) of about 97 % [2226, 32]. About 3 % diagnostic error is attributed to improper sampling, technical error, interpretation inaccuracies, and error in communication. It is to be noted that the incidence of false-positive result is about 1 % [56]. Even with this high diagnostic accuracy rate, the frozen section needs to be used judiciously. Chathurvedi et al. [27] have questioned the value addition of frozen section over clinical examination, i.e., can frozen section detect lesions that could not have been detected clinically?

  1. (a)
    Frozen section of surgical margins: The goal of this procedure is to ensure that surgery has removed the microscopic tumors from all the margins. Different institutions and surgeons have varying policies in handling the surgical specimens for frozen section to determine adequacy of surgical resection. (1) Send the entire specimen to the pathologist after insertion of orientation stitches. (2) Send additional circumferential margins from all around the resection bed and request frozen section of the re-excised tissue. (3) Margins from five to six regions of the surgical bed (medial, lateral, anterior, posterior, deep), or (4) margins from areas of close or suspicious margins. Considering the efforts required for the pathologists to process the tissue and to minimize interference with final pathology and normal tissue, option 4 or 5 is commonly practiced. It is essential that the tissue is appropriately labeled so that the frozen section result can be used effectively for further treatment decision making.
    Although frozen section to permanent section concordance is over 97 %, there are areas of potential pitfalls in selected scenarios. Dysplastic lesions, which are difficult to interpret even by permanent sections, cannot be reliably evaluated by frozen section. Differentiation of pseudoepitheliomatous hyperplasia resulting from augmented tissue response to irritants can clinically mimic squamous cell carcinoma. The pathologic differentiation is based on cellular atypia and connective tissue invasion. These features are difficult to determine by frozen section. Another scenario is differentiating postradiation changes from recurrent carcinoma. Although clinical and histologic features of acute radiation changes are nearly impossible to distingush from persistant carcinoma, it is rarely a practical issue as biopsy or surgical salvage are rarely carried out during the immediate post-radiation period. About 2 months after radiation, typical features of radiated oral mucosa can be appreciated. Recognizing these well-described features can help to distinguish persistent or recurrent tumors from radiation changes. These include atrophy of epithelium, cellular atypia, pseudoepitheliomatous hyperplasia of the minor salivary glands, squamous metaplasia of the salivary gland ducts, endothelial cell hypertrophy, and atypical fibroblasts.
  2. (b)
    Intraoperative decision making: Frozen section is used in deciding what critical structures are to be sacrificed. This includes the margin from the carotid sheath and the tissue adjacent to the mandible or within the bone marrow to determine bone and perineural invasion along the nerves. Mandible of cranial nerves carries major morbidity frozen section is often employed to determine the tumor invasion status. It is to be noted that though the frozen section of the bone may not be feasible in many centers, imprint cytology or curettage from the marrow can help to determine adequacy of the bony margin. Other clinical scenarios include surgical margin around contralateral lingual artery during resection of advanced oral tongue carcinoma to determine whether the patient requires total glossectomy and margin status at the vallecula to determine the feasibility of larynx preservation with total glossectomy.
  3. (c)
    Lymph nodes: Although macroscopic involvement of lymph nodes with squamous cell carcinoma can be determined with about 99 % accuracy, it cannot accurately detect lymphoma. Frozen section may be used to determine the extent of neck dissection. Intraoperative detection of metastatic node in level 4 may assist the decision to convert selective neck dissection to modified radical neck dissection [29, 30]. Frozen section has limited or no value in sentinel lymph node biopsy that attempt to identify small foci of metastatic disease. With macrometastasis (>0.2 mm), frozen section examination and imprint cytology of the lymph nodes were found to have similar diagnostic accuracy. The detection of micrometastasis (<0.2 mm) or isolated tumor cells requires serial step sectioning at every 2 mm and perhaps immunohistochemistry for cytokeratin [43].

6.2.3 Frozen Section Versus Clinical Examination

There is now considerable body of literature to substantiate that routine use of frozen section has very limited role in the management of oral squamous cell carcinoma. Chaturvedi et al. [27] in a prospective trial of 145 patients undergoing surgery for head and neck squamous cell carcinoma found that frozen section identified 83 % (n = 64) of 565 mucosal and 104 soft tissue margins as positive of invasive carcinoma. This compromised surgical margin was associated with gross clinically close margin of less than 7 mm. They therefore recommend that there is no value in doing frozen section if the gross clinical margin is more than 7 mm. Similar findings has been reported by many authors demonstrating lack of clinical benefit for routine use of frozen section [23, 26, 32].
Based on the current evidence, Chaturvedi et al. [27] recommended a clinical decision making algorithm (Fig. 6.4). When frozen section is carried out, it is best to be performed from the surgical bed rather than the surgical specimen. The region of where the frozen section was taken should be accurately marked in relation to the primary resection specimen, so that appropriate and accurate intraoperative or postoperative decision can be made.

Fig. 6.4

Intraoperative treatment decision making based on gross clinical examination and frozen section examination (Chaturvedi et al. [27])

6.2.4 Circumferential Excision Versus Compartmental Resection

Traditional method of surgical excision of primary oral cavity squamous cell carcinoma is carried out using the principle of wide local excision with 1 cm normal tissue away from the visible and palpable tumor boarders. Even with apparent negative surgical margin, 30 % of oral cancer fails locally [9]. As stated above, although various biological factors such as pattern of invasion and perineural invasion may contribute to the development of local recurrence, surgical technique may be modified to improve the local disease control rate.
Compartment resection is based on the observation that tumor does not necessarily advance in a concentric fashion but follows pathways of least resistance. This is determined by anatomic structures that either facilitate invasion of tumors such as orientation of muscle fibers, nerve sheath, lymphatics and blood vessels, and structures that offers resistance to tumor invasion such as periosteum and fascia [33, 34]. It is to be noted that ablative surgery that cause discontinuation of a muscle, nerve or blood vessel will have similar functional consequences whether it is remove in part or complete. This formed the basis of compartmental resection that attempted to remove “anatomic compartments” that are involved by cancer. This concept is well established in soft tissue sarcoma surgery of extremities. It has been shown by Azzarelli et al. [35] in a series of 471 patients with extremity sarcoma that compartmental resection yielded significantly better local control rate of 76 % in comparison to 53 % with wide excision. Compartment resection needs to be distinguished from radical Halstedian principle that entails ultraradical excision of tumor and normal tissue of the affected organ disregard to the pattern of invasion of the tumor.
Technique of compartmental resection has been developed for advanced oral tongue [44] and gingivo-buccal carcinoma [31]. In a series of 193 patients with oral tongue carcinoma, Calabrese at al. [45] reported 88.4 % local control rate with compartmental resection in comparison to 71.6 % with conventional surgery. It is to be noted that the concept of compartment resection has application only in moderate to advanced tumors (T2–T4) of oral cavity that involve discernible anatomic units.

6.2.5 Surgical Access to Oral Cavity

Optimal exposure of the tumor is required for intraoperative examination, with maneuvering of instrumentations to achieve three-dimensional excision with uninvolved margins. In addition, the exposure should facilitate optimal reconstruction of the surgical defect. The commonly used methods to oral cavity tumors are peroral, lip split with mandibulotomy, lower cheek flap, visor flap, and upper cheek flap approaches and for advanced gingivo-buccal tumors with skin involvement, extension of the skin incision around the primary tumor excision to the neck (Fig. 6.5). The choice of approach depends on the site and extent of the tumor invasion, the need to remove a part or a segment of maxilla or mandible, dental status, and degree of mouth opening.

Fig. 6.5

Choice of approaches to oral cavity (a) peroral, (b) lower lip split, (c) upper lip split, (d) lower lip split with mandibulotomy, (e) visor flap
Many traditional approaches need to be reevaluated in the context of improved instrumentation, high-speed bone cutting instruments with varying geometry, and improved visualization with fiber optic lighting and endoscopes. These technologic advances have lead to the development of the field of minimally invasive surgery that has revolutionized many surgical fields, limiting morbidity of procedures. In the head and neck region, the impact of which is most apparent in skull base and laryngeal tumors. With the assistance of endoscopes, powered instruments, and lasers, one can safely resect tumors from these critical areas through a natural opening of less than 2 cm in size. It is paradoxical that in the surgical management of oral cavity tumors with the availability of about 4 × 4 cm mouth opening, one often resorts to transcutaneous approaches. It is to be noted that almost all orthognathic surgeries that require osteotomy of maxillofacial skeleton from the mandibular condyle to the symphysis and from Lefort-1 to Lefort-3 are carried out almost exclusively through peroral approaches. Many instruments that are used for craniofacial surgery can be adapted for oral cavity cancer surgery. Peroral Approach to Oral Cavity

Tumors of anterior tongue, buccal mucosa, floor of mouth, and alveolus that are either T1 or T2 stage with adequate mouth opening are considered ideal candidates for peroral excision [36]. However, there are recent studies attesting the feasibility of peroral excision for moderately advanced oral cancer (T2, T3) [46]. In a series of 79 consecutive patients with T2 and T3 oral cancer, they have demonstrated that peroral excision achieved comparable pathologic uninvolved margin status (81 %) as transmandibular procedures. This was true for patients undergoing marginal or segmental mandibulectomy as well as posterior oral cavity tumors such as retromolar trigone cancers. Combining transcervical and peroral approach, without lip split, the incidence of deep soft tissue margins was also found to be comparable to that of open approaches. Sutton et al. [39] also have reported the lack of difference in surgical margin status based on the surgical approaches. In the series of Battoo et al. [46], 53 out of the 79 patients underwent suceesful free tissue transfer supporting the view that peroral excision does not limit exposure for appropropriate oral cavity reconstruction. Mandibulectomy Approach

The primary indication for mandibulectomy approach is to resect tumors of the base of tongue or oropharynx. However, the technique also needs to be employed in situation where there is limited mouth opening. The need for marginal or segmental mandibulectomy is a contraindication of the technique. Though mandibulotomy can be performed as median (at the midline), paramedian (medial to mental foramen), or lateral (posterior to mental foramen), because of the least disruption to genioglossal muscle and mental nerve, paramedian mandibulotomy is preferred as the most optimal approach to posterior oral cavity and oropharynx. Step osteotomy was recommended in the past for improved stability of osteotomy in the era of less stable fixation techniques; however, with the availability of rigid fixation, it is rarely needed. Two 2.0 mm mini plates should be preadapted and screws inserted prior to mandibulotomy. The superior boarder plates should be fixed with mono-cortical screws and inferior boarder plates fixed with bicortical screws. Care should be taken to avoid injury to the mental nerve. During replating of preadapted plates, occlusion should be maintained either with manual pressure or with the aid of intermaxillary fixation (Fig. 6.6).

Fig. 6.6

Type of mandibulotomy and fixation technique. (a) Types of mandibulotomy, (b) clinical case of paramedian mandibulotomy performed between canine and first premolar teeth. Care was taken to preserve mental nerve and insertion of digastric muscle, (c) Technique of fixation of mandibulotomy with two mini-plates, The upper plate is fixed with mono-cortical screws and lower plate with bicortical screws Lower Lip Split

The mandibulotomy needs to be combined with lower lip-split incision. Several modifications of the lower lip split have been introduced to improve aesthetic and functional results. These are (1) straight midline incision (Roux-Trotter), (2) straight midline with Z-plasty at labiomental crease (Kuriakose), (3) lateral lip split (Robson), (4) straight midline with chin contour (McGregor), and (5) straight midline with chin contour and vermilion and submental Z-plasty (Hayter) (Fig. 6.7) [60]. analyzed functional and aesthetic results of various incisions. They observed comparable aesthetic and functional results among the four groups except that the lateral lip split had worst outcome. The minor differences they observed were with respect to straight midline incision showing more vermilion notching compared to other incisions. The lip skin appearance was better with straight midline with chin-contour and vermilion and submental Z-plasty incision. Lip sensation was better with straight midline. However, the lip movements and oral incompetence was better with straight midline with chin-contour and vermilion and submental Z-plasty incision. To combine the advantages of all the incisions, a straight midline incision with Z-plasty at labiomental crease appears to give optimal result. As noted in Rapidis study, irrespective of type of incision, meticulous approximation of the vermilion boarder and muscles is essential to minimize aesthetic and functional impairments.

Fig. 6.7

Lower lip-split techniques: (a) straight midline, (b) midline with Z-plasty at labiomental crease, (c) lateral lip split, (d) straight midline with chin contour, (e) straight midline with chin contour and Z-plasty at vermilion and submental region Lower Cheek Flap

The lip-split incisions described above without mandibulotomy is used for patients requiring either marginal mandibulectomy or segmental mandibulectomy. As this approach deinnervates the lower lip sensation, it is to be avoided in patients where sacrifice of mental nerve or inferior alveolar nerve is not required as part of the ablative procedure. The only exception could be in patients with significant trismus often encountered in patients with associated oral submucous fibrosis. Visor Flap

The visor flap involves elevation of bilateral upper cervical flap to the lower boarder of mandible and to drop tongue and floor of mouth to the neck after performing release incision along the mandibular alveolus or along with marginal mandibulectomy. This approach is used primarily to perform total or near-total glossectomy required for advanced oral tongue cancer. Whenever possible, attempts should be made to preserve or reattach anterior belly of the digastric muscle to the symphysis of mandible. It allows dynamic laryngeal suspension that is required to prevent aspiration following total laryngectomy.
Visor flap was also attempted to manage the floor of mouth cancer by releasing the flap over the mandible after placing releasing incision along the labial and buccal sulcus. This though avoids lower lip split, causing paresthesia of the lower lip, with major functional consequences. Therefore, this approach is no longer recommended. Upper Cheek Flap

Upper cheek flap is primarily used to expose carcinoma of posterior maxillary alveolus as well as tuberosity of the maxilla. Thankappan et al. [47] have described modification of the upper cheek flap designed to conform to aesthetic and functional subunits of face. This involves four critical modifications: (1) The midline upper lip incision is extended into the anterior nares. (2) From the anterior nares, the incision is extended superiorly along the alar cartilage to the junction dorsal and lateral nasal subunit. (3) The incision is further extended superiorly between the dorsal and lateral nasal subunits to the medial canthus region and (4) a Z-plasty at the medial canthus region, which is extended superiorly as Lynch extension or inferiorly as infraorbital incision (Fig. 6.8).

Fig. 6.8

Upper lip-split technique: (a) midline upper lip, (b) midline along philtrum ridge, (c) lateral rhinotomy with lower eyelid extension, (d) aesthetic subunits of the face, (e) modification of incision based on aesthetic subunit principle. (f1) incision design of modified lateral rhinotomy, (f2) view after wound closure, (f3) wound appearance one week after surgery Exposure of Oral Cavity Tumor with Skin Involvement

Gingivo-buccal cancer has propensity to involve cheek skin, which needs to be removed in many advanced tumors. If this is required, the skin incision around the tumor can be extended to the neck incision, which will give adequate excision of the primary tumor as well as exposure of the neck to perform neck dissection (Fig. 6.9). For smaller skin defects, the incision can be modified to incorporate a large cervical rotation flap that can offer both exposure for surgical excision and neck dissection and provision of cover for the skin defect (Fig. 6.10).

Fig. 6.9

Composite resection with overlying facial skin
Jun 24, 2017 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Surgical Management of Oral Squamous Cell Carcinoma
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