Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

Surgical anatomy of the buccal region

• The buccal mucosa:
  • Is the mucosal lining of the inner surface of the cheek
  • The area extends from:
    • The oral commisure anteriorly to the retromolar trigone posteriorly:
      • The junction between the buccal mucosa and retromolar trigone:
        • Is an arbitrary line drawn from the maxillary tuberosity to the distobuccal aspect of the mandibular third molar (or its anticipated position if not present)
  • The inferior and superior boundaries of the area are delineated by:
    • The mandibular and maxillary gingivobuccal sulci, respectively
• The buccal mucosa is not exposed to masticatory loads:
  • So is covered by a lining mucosa with nonkeratinizing stratified squamous epithelium:
    • The mucosa is firmly attached to the underlying buccinator muscle
    • Minor salivary glands are located within the cheek (submucosa)
• The parotid duct:
  • Pierces the buccinator muscle to enter the oral cavity adjacent to the second maxillary molar tooth
• Sensory innervation to the area:
  • Is via the buccal branch of the mandibular division of the trigeminal nerve
• Lymphatic drainage of the site:
  • Is via the ipsilateral facial and submandibular nodes:
    • To the deep cervical chain
• The thickness of the cheek, from mucosal lining to external skin:
  • Is 1 cm to 3 cm
• Epidemiology
  • The buccal mucosa is the most common site for oral cancer:
    • In South East Asia:
      • Up to 40% of oral cancers arising at this site
    • This contrasts with North America and Western Europe:
      • Where buccal carcinoma only accounts for 2% to 10% of oral carcinomas
  • The consumption of betel quid:
    • Is socially and culturally embedded in the countries of South East Asia:
      • It is responsible for the difference in site predilection
    • The ingredients of betel quid (paan / paan masala) varies throughout South East Asia:
      • The main ingredients include:
        • The piper betel leaf
        • Slaked lime
        • Spices
        • Tobacco
        • Areca nut
    • For many years, the tobacco content alone was credited as being the carcinogenic agent in betel quid:
      • However it is now recognized that the areca nut is also carcinogenic:
        • As well as being the main etiological agent in:
          • Oral submucous fibrosis
      • Individuals who consume betel quid frequently have a preference regarding which side they chew betel:
        • This corresponding to the side of tumor development
      • There is a strong association with smoking and alcohol consumption:
        • In populations where betel chewing is not prevalent
• The male-to-female ratio:
  • In Western countries approximates 1:1:
    • However in South East Asia the ratio reflects the consumption of betel quid
  • In India, the male-to-female ratio:
    • Is approximately 4:1
  • In the Taiwanese population, where betel quid use occurs primarily in the male population:
    • The ratio may be as high as 27:1
• Buccal carcinoma typically occurs over the age of 40 years:
  • Although it may occur in younger patients:
    • Particularly when associated with the habit of betel chewing
• Presentation:
  • Buccal carcinoma may be described as:
    • Verrucous, exophytic or ulceroinfiltrative in character

• Presentation of buccal carcinoma of the oral cavity:
  • Patients may present with:
    • Pain
    • An intraoral mass
    • Ulceration
    • Trismus
  • Patients who chew betel often have areas of:
    • Erythroleukoplakia of the buccal mucosa or submucous fibrosis and consequent trismus:
      • Making the detection of invasive squamous cell carcinoma difficult
  • Advanced buccal carcinomas may extend into adjacent sites to include:
    • External skin, mandible or maxilla
  • It is not unusual for patients to present with advanced disease:
    • 40% or more presenting with stage III / IV disease
    • Palpable lymphadenopathy on presentation:
      • May be as high as 57% for T3 / T4 lesions
    • Occult nodal metastasis:
      • May be present in 26% of those who are clinically N0 at presentation:
        • Tumors greater than T2, are poorly differentiated, have a poor lymphocytic response or are thicker than 5 mm:
          • Are more likely to demonstrate cervical metastasis
      • Tumors are usually well differentiated
• Work up:
  • Biopsies of buccal carcinomas should be of sufficient depth to help the pathologist give an indication of depth of invasion:
    • Since this will help decide on management of the neck
  • Buccal carcinoma may rapidly extend to adjacent sites:
    • Thus accurate imaging is required:
      • Most patients will require MRI / CT imaging:
        • Augmented with ultrasound scan if necessary to help in the assessment of depth of primary and cervical lymphadenopathy
• Treatment
  • Primary site:
    • Traditional treatment of buccal carcinoma is:
      • Surgery with postoperative radiation therapy (PORT) for selected patients
    • T1 / T2 disease:
      • Can typically be resected perorally
    • T3 / T4 disease:
      • May require facial access incisions and bony resection of the maxilla and / or mandible
    • The primary tumor should be resected with:
      • A 1 cm margin and up to 2 cm if skin is involved
      • The buccinator muscle:
        • Should be included as the deep margin at the very least
      • The parotid duct:
        • May need to be repositioned or ligated
      • External skin should be taken with the specimen:
        • If there is any evidence clinically or on imaging that it is involved
      • Partial maxillectomy or mandibular resection (rim (marginal) or segmental) may be required.
    • Small T1 tumors:
      • May be resected and reconstructed by primary closure
      • Healing by secondary intention may be considered:
        • However postoperative trismus may be anticipated:
          • Unless vigorous mouth opening exercises are conducted
      • Split thickness skin grafts may be used:
        • The use of silicone sheets to stabilize the graft being useful
        • The use of a skin graft to reconstruct deeper resections:
          • May leave a very thin cheek with potentially poor aesthetics
      • Local flaps such as:
        • The buccal fat pad or temporoparietal fascial flap:
          • May be used for reconstruction if tumor extension does not compromise their use
      • Microvascular free flap reconstruction with a radial free forearm flap or anterolateral thigh flap:
        • Restores the thickness of the cheek and if external skin is involved:
          • The flaps can be bipaddled to provide reconstruction of mucosal and skin surfaces
    • T4 tumors requiring segmental resection of the mandible:
      • May require composite free flap reconstruction
    • Reconstruction with a radial free forearm flap:
      • Has been shown to give better postoperative mouth opening than reconstruction with a split skin graft or buccal fat pad

• Radiotherapy:
  • As a single treatment modality for T1 / T2 tumors has been advocated:
    • However, a change of practice from radiotherapy to surgery at Memorial Sloan Kettering Cancer Center was associated with improved prognosis
  • Brachytherapy or external beam irradiation may be considered
• Management of the Neck:
  • Regional spread of disease in buccal carcinoma is usually to:
    • The ipsilateral level I and II lymph nodes
  • Patients with palpable lymphadenopathy or pathological nodes on imaging:
    • Should have a comprehensive neck dissection:
      • Although if pathological nodes are only located in level I, a level I to III selective neck dissection (SND) may be considered
    • Nodes in the region of the facial artery as it crosses the mandible:
      • Should be removed with the neck dissection specimen
  • Patients with a cN0 neck:
    • With a T2 or greater primary tumors or tumors with a thickness greater than 5 mm:
      • Should have an elective neck dissection:
        • Some institutions will conduct an elective neck dissection (END) if the tumor is 3 to 4 mm thick or if histological examination of the tumor demonstrates lymphatic infiltration
• PORT:
  • The indications for postoperative radiotherapy to the loco-regional area are similar to other sites:
    • Notably two or more nodes in the neck, extracapsular spread (ECS), positive margins or stage III / IV disease
  • The beneficial role of PORT in selected patients with buccal carcinoma has been demonstrated by several authors:
    • Some authors suggest that PORT should be considered even in stage I and II disease, or tumors greater than 10 mm thick
• Recurrence:
  • Recurrence rates for buccal carcinoma are 26% to 80%:
    • Usually occurring within two years
  • Involvement of the parotid duct and buccinator muscle:
    • Have not been found to be significant indicators of recurrence
  • Factors that influence recurrence include:
    • Tumor thickness and tumor differentiation

• Outcomes and prognosis in ILC are generally favorable:
  • Consistent with the luminal A phenotype
• The majority of evidence supporting similar or better survival as IDC:
  • These include a large SEER study of 263,408 women (27,639 with ILC and 235,769 with IDC) treated between 1993 and 2003:
    • A stage-matched analysis showed that ILC was more likely to be:
      • Greater than 2 cm
      • Lymph node positive
      • ER positive
    • The 5-year disease-free survival was significantly better for ILC than for IDC after matching for stage:
      • With an overall 14% survival benefit (HR 0.86) identified on multivariable analysis
    • As such, although overall stage-corrected prognosis appears to be favorable, some propose that this may be offset by a higher stage at presentation and higher rates
      of late metastatic recurrences, often occurring in atypical sites
  • The pleomorphic subtype of ILC is:
    • Also a known exception to the generally favorable prognosis, having been shown in retrospective series to more frequently develop metastatic disease than other nonpleomorphic ILCs
• Currently, there are no unique specifications for surveillance of ILC:
  • For all treated nonmetastatic breast cancers, NCCN guidelines recommend a history and physical examination one to four times per year as clinically appropriate for 5 years and then annually
  • Annual mammography should be performed for patients treated with BCT
  • The role of MRI in surveillance is unclear and presently recommended only for those with a lifetime risk greater than 20% of developing a second primary breast cancer
• Adherence to hormonal therapy should be encouraged for those prescribed and yearly gynecologic assessment arranged for those without a previous hysterectomy
• Signs of disease recurrence, either locoregional or systemic, should prompt evaluation with appropriate laboratory work and diagnostic imaging, which may include diagnostic
  CT or fluorodeoxyglucose PET/CT scans followed by biopsy to prove first recurrence of disease
• It should be noted that the generally low-grade nature of ILC may limit the sensitivity of traditional PET/CT scans, and studies are ongoing for the use of alternative radiotracers using ER ligands for
  increased sensitivity
• Confirmed LRRs (those of the breast / chest wall and / or regional lymph nodes alone):
  • Can be managed with complete surgical resection and systemic therapy
• Distant metastatic disease (stage IV) is managed with individualized systemic therapy

• Considerations for radiation therapy (RT) in locoregional control, once more generally common among the ductal and lobular cancer types, are summarized here (Figure)
• Adjuvant whole breast RT:
  • Reduces the risk of both local regional recurrence (LRR) and death from breast cancer after BCS and is a necessary element of BCT
• Additional regional nodal irradiation:
  • May also be indicated for those with involved lymph nodes or high-risk tumors
• It is noteworthy that it may be acceptable to omit RT:
  • Among elderly women with select low-risk, ER-positive tumors:
    • Data to support this include the Cancer and Leukemia Group B (CALBG) 9343 randomized trial of women age 70 years or older with stage I ER-positive cancers treated with lumpectomy and tamoxifen with or without RT:
      • Which demonstrated no advantage in
        overall survival:
        • Although there was a small improvement in LRR among those treated with RT
• Accelerated partial breast irradiation (APBI):
  • Is a newer technique involving more focused RT
    delivered in higher doses over a shorter time span
  • Notably, the recent American Society for
    Radiation Oncology (ASTRO) guideline update cites lobular histology as a criterion for “cautionary” use of APBI outside of a clinical trial
• Postmastectomy RT:
  • May also benefit selected patients, a decision generally made by consideration of the presence of:
    • Macrometastatic nodal involvement
    • Large tumor size
    • High-risk disease features
  • It is important to note that the implications of margins at mastectomy remain controversial among radiation oncologists, and there are no data to support a definite benefit of postmastectomy RT in patients with close margins
  • Similar to surgical and systemic therapy trials, ILC patients comprise a minority in postmastectomy RT trials
  • A recent study using Survival, Epidemiology, and End Results (SEER) data including 12,703 ILC patients treated from 2004 to 2009, of which 26% had a definite indication for postmastectomy RT:
    • Found an improvement in 5-year overall survival and disease-specific survival from 80.9% to 84.7% (p = .0003) among ILC patients, a benefit to the same degree as IDC:
      • These data support continued decision
        making for radiotherapy using existing criteria, regardless of cancer histology

• What lymph node levels does a lateral [therapeutic] neck dissection for differentiated thyroid cancer (DTX) include?
• Although the rate of clinical nodal involvement in the lateral compartment was initially described by the Japanese (Noguchi et al. 1970) and Germans (Gimm et al. 1998):
  • Sivanandan et al (2001) were the first to systematize it by levels
• In 2013, the Canadian group of Jeremy L. Freeman (Eskander et al. Thyroid) conducted a systematic review that included the meta-analysis of 18 publications (including his 2012 retrospective work with 185 patients; Merdad et al. Head Neck) agglutinating 1298 lateral neck dissections for DTC:
• Emptying of sublevel IIb (retrospinal recess):
  • Is usually indicated when clinical, radiological or macroscopic involvement:
    • Is evident intraoperatively
  • Macroscopic involvement evident in the intraoperative sublevel IIa:
    • Usually determines the addition of sublevel IIb to the neck dissection
• “Skip metastases” within the lateral compartment are uncommon and occur in around 9% of patients:
  • Level II with level III and IV
  • Level V with level III and IV
    • (Merdad et al. 2012)
• Selective lymphadenectomy IIa to Vb:
  • Currently dissects levels IIa, III, IV, Vb and the “infraspinal” portion of the VA [VAi] in order to avoid the functional sequelae of cranial nerve XI dissection
• Although heterogeneity was a constant in all comparisons by levels (I2: 31% to 87%), it is the best evidence to date that justifies the use of selective emptying IIa-Vb in this cohort of patients with this pathology:
  • Level III is the most frequently compromised
• The majority (73%) of patients have more than one level involved:
  • Level III and IV: 46%
  • Level II, III and IV: 26%
  • Level III, IV and V: 11%
  • Level II, III, IV and V: 13%
    • (Merdad et al. 2012)
  • Levels I and sublevel Va (cranial to the distal spinal nerve pathway):
    • Are rarely involved, usually in patients with high disease volume and multilevel invasion

• The list of cancer-associated genes continues to expand, and it is therefore increasingly important to obtain a thorough family history to assess any potential for hereditary cancer syndromes:
  • The BRCA1 and 2 genes account for the majority of hereditary breast cancer cases
• The BRCA1 gene is located on chromosome 17q21:
  • It is part of the DNA repair pathway:
    • Functioning as a tumor suppressor gene
  • Presence of a deleterious BRCA1 mutation is associated with:
    • A lifetime breast cancer risk of:
      • 72% by age 80
    • A lifetime ovarian cancer risk of:
      • 44%
  • In addition, BRCA1 mutations have been associated with:
    • An increased risk of pancreatic cancer and melanoma
  • BRCA1 associated breast cancers:
    • Tend to occur at younger ages and are more likely to have aggressive phenotypes compared to non-BRCA-associated tumors
• Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome:
  • Is caused by genetic mutations in the mismatch repair system:
    • With the most common associated gene mutations being MLH1, MSH2, MSH6, and PMS2
  • Lynch syndrome is the most common hereditary form of colorectal cancer, and is also associated with an increased risk of:
    • Endometrial, urogenital, pancreatic, biliary tract and ovarian cancers:
      • Women with Lynch syndrome have a 20% to 60% lifetime risk of endometrial cancer
• Germline mutations in the PTEN gene:
  • Are associated with Cowden syndrome:
    • Characterized by the formation of multiple hamartomas as well as an increased risk of:
      • Breast, endometrial, non-medullary thyroid, and renal cell cancers
• Hereditary diffuse gastric cancer syndrome:
  • Is associated with a mutation in the CDH1 gene
  • It leads to an increased risk of early onset gastric cancer and lobular breast cancer
• PALB2 is a breast cancer susceptibility gene:
  • With an estimated breast cancer risk of 45%:
  • PALB2 mutations have also been reported to increase the risk of:
    • Ovarian cancer and possibly pancreatic and prostate cancer
• BRIP1 mutations:
  • Have been shown to confirm a high-risk of ovarian cancer (OR 20.97), but no increase in breast cancer risk
• References
  • Shulman LP. Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome. Obstet Gynecol Clin North Am. 2010;37(1):109-133, Table of Contents.
  • Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. Jama. 2017;317(23):2402-2416.
  • Mersch J, Jackson MA, Park M, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269-275.
  • Southey MC, Winship I, Nguyen-Dumont T. PALB2: research reaching to clinical outcomes for women with breast cancer. Hered Cancer Clin Pract. 2016;14:9.
  • Weber-Lassalle N, Hauke J, Ramser J, et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res. 2018;20(1):7.

• Papillary thyroid cancer (PTC):
  • Has a high predilection for spread to locoregional lymph nodes (LNs):
    • Occurring in up to 40% to 90% of cases:
      • When prophylactic nodal dissection is performed:
      • Though such high rates of metastatic disease may prove enticing to recommend routine prophylactic node dissection:
        • Recurrence-free survival is not effected by the removal of sonographically normal, microscopically diseased nodes
      • Instead, prophylactic central neck dissection may be individually considered for those patients with:
        • T3 or T4 tumors, or in the presence of lateral neck metastases
      • Clinically suspicious or biopsy-proven nodal disease warrants a “therapeutic” dissection of the involved compartments
        • “Berry picking,” or selective removal of suspicious LN metastases, is not recommended:
          • As it is associated with significantly higher recurrence rates and does not lower the rate of postoperative complications compared with systematic compartmental dissections
• The risk of surgical complications with nodal dissection should be weighed against the benefit of LN removal:
  • Central neck dissections may result in temporary or permanent injury to the RLN and hypoparathyroidism
  • Surgeon case volume predicts patient outcomes:
    • Those performing less than 10 cases compared with those performing more than 100 cases per year had complications in 24% and 14.5% of cases, respectively
  • Although dissection of the lateral neck is less often associated with adverse events:
    • Injury to the spinal accessory nerve may occur with dissection of level II or V
  • Similarly, chyle leaks may be seen after removal of nodes in level IV:
    • Particularly on the left side

• Historically:
  • Almost all patients were given thyroid hormone:
    • To fully suppress serum thyroid-stimulating hormone (TSH)
  • The rationale for this approach:
    • Was based on the theory that TSH is a stimulant for thyroid cell proliferation and suppression of thyrotropin will inhibit tumor growth:
      • Indeed, early studies supported the role of TSH suppression in reducing the likelihood of disease progression and improving survival:
        • Particularly in those with high-risk disease
      • More recent analyses, however, have failed to demonstrate a benefit of such suppressive therapy in those with low-risk tumors:
        • In fact, such treatment may prove harmful
      • A long-term observational study showed a three-fold increased risk of cardiovascular death for each ten-fold reduction in mean TSH level
      • Patients with subclinical thyrotoxicosis:
        • Are also at increased risk of atrial fibrillation, ventricular hypertrophy, diastolic dysfunction, and impaired cardiac reserve
        • Additionally, bone turnover may be adversely affected by suppressive doses of levothyroxine:
          • Higher rates of osteoporosis may be seen in thyroid cancer patients:
            • There is an increased risk of fracture when suppressive doses of levothyroxine are used
  • As a consequence of the myriad negative effects of excess levothyroxine:
    • The target TSH range should be determined on an individual basis
    • It is also worthy of note that lowering TSH to undetectable levels probably does not confer additional benefit beyond that seen with less aggressive suppression below 0.1 mU/L
    • The optimal TSH range should consider the initial risk for recurrence, the response to therapy, and the risk for thyrotoxicosis-related morbidities in the individual patient
    • Furthermore, this target TSH for the individual patient may evolve over time, depending on the response to therapy

• Excellent Response to Therapy:
  • Patients with no biochemical (unstimulated serum thyroglobulin (Tg) < 0.2 or stimulated Tg < 1.0 ng/mL) or radiographic evidence of disease are classified as having an excellent response to therapy
  • Patients with an initial low to intermediate risk of recurrence who meet these criteria:
    • Are recommended to have serum Tg monitored every 12 to 24 months
  • Patients with initially high-risk disease:
    • Should continue to have a serum Tg measurement at least every 6 to 12 months
• Biochemical Incomplete Response to Therapy:
  • Patients who have undergone total thyroidectomy and remnant ablation and have an unstimulated serum Tg > 1 ng/mL or a stimulated Tg > 10 ng/mL or a rising thyroglobulin antibody (TgAb) titer with negative imaging:
    • Are classified as having a biochemical incomplete response to therapy
  • Such patients should undergo imaging with sonography of the neck:
    • If the disease is unable to be located:
      • Cross-sectional imaging of the neck and chest should be performed
  • Serum Tg should be followed at least every 6 to 12 months.
• Structural Incomplete Response to Therapy:
  • Those patients with structurally or functionally (on diagnostic whole-body scan [DxWBS] or 18(FDG-PET) evident disease are classified as:
    • Having a structural incomplete response to therapy
  • Unfortunately, the majority of patients in this category will have persistent disease in spite of additional treatments
  • Disease-specific death rates are high in this group:
    • 11% with locoregional metastases
    • 50% with distant metastases
• Indeterminate Response to Therapy:
  • Patients with biochemical or structural findings that cannot be confidently classified as either excellent response or persistent disease:
    • Are deemed as having an indeterminate response to therapy
  • Such patients may be carefully followed with biochemical testing and serial imaging to better delineate which category is ultimately appropriate
  • It is estimated that up to 20% of these patients will eventually develop conclusive evidence of disease requiring additional therapy