17 Recurrent Squamous Cell Carcinoma of the Oral Cavity

Russell B. Smith, Gerry F. Funk, and Henry T. Hoffman

Of all the new malignancies affecting the head and neck each year, 30% will involve the oral cavity.1 Squamous cell carcinoma will be the predominant histopathology in these cases.² Treatment of oral cavity carcinoma is determined by many factors but is influenced most notably by the anatomical extent of the lesion and the preference of the treating institution. In general, similar cure rates for early-stage disease (stage I or II) result following initial treatment with either surgery or radiation therapy.^1,2 Despite the similar cure rates obtained with surgery and radiation therapy, most early oral cavity carcinomas are treated by surgical excision to avoid the long-term complications associated with primary radiation therapy of the oral cavity, which include xerostomia and osteoradionecrosis. Advanced-stage disease (stage III or IV) is usually treated with combined modality therapy using surgery and postoperative radiation therapy.^1,2 Nonsurgical therapy consisting of chemoradiation for advanced oral cavity carcinomas at this point has not been routinely employed. Recurrences often occur despite appropriate initial therapy, especially with advanced-stage disease. We will review the evaluation and management of locally recurrent squamous cell carcinoma of the oral cavity.

Recurrences

The appearance of tumor within the oral cavity after previous cancer therapy can be classified into three categories: persistent disease, recurrent disease, and a second primary. Persistent disease is defined as tumor that had an incomplete response to definitive therapy or tumor that appears within 6 months of definitive therapy after a brief disease-free interval. Recurrent disease is defined as tumor that occurs after at least a 6-month disease-free interval. A second primary is a tumor that is identified in a distinctly separate location from the original tumor. These lesions may be difficult to differentiate from recurrent disease if the lesion is adjacent to an area of previous tumor. Time is also an important consideration when classifying a tumor as a recurrence or a new primary in that most recurrences will occur within 18 to 24 months post-treatment, and lesions that occur 4 to 5 years after initial therapy, even if in the same location, are more likely a second primary tumor. Literature on recurrent oral cavity carcinomas rarely differentiates persistent from recurrent disease, and both are reported as recurrent disease.

Recurrence rates for squamous cell carcinoma of the oral cavity have been reported to be between 20 and 73% when all stages are included.^3–7 These recurrences may occur locally, regionally, distantly, or as a combination of locations. The reported patterns of recurrence vary, with some reporting local recurrences occurring in nearly 60% of cases, whereas others note regional recurrences as being most common.^4–7 Fu et al reported an even distribution between local, locoregional, and regional recurrences.⁸

Multiple risk factors for local recurrence have been identified for oral cavity carcinomas. Yuen et al noted a linear increase in local recurrences based on advancing T-classification, with 16% of T1 lesions and 46% of T4 lesions developing local recurrences.⁵ In a series of 51 patients with predominantly early-stage tongue carcinomas that had been treated by surgery with or without adjuvant therapy, Kirita et al found tumors with an endophytic growth pattern, grade 4 histologic pattern (diffusely infiltrating) of invasion, and surgical margins < 5 mm/positive margins to have a higher local recurrence rate.³ El-Husseiny et al noted that in addition to positive margins, T4 tumors and tobacco use were associated with a higher recurrence rate.⁹ It was also noted that the small cohort of patients with T3 and T4 tumors treated with irradiation alone had a high local recurrence rate. This is similar to the results of Leung et al.¹⁰ Jones et al determined positive margins and tumor depth > 5 mm each independently increased recurrences by 3-fold, whereas tumor differentiation and the presence of desmoplasia, perineural spread, capillary lymphatic space invasion, and inflammatory response had no impact on recurrence.¹¹ Van Es et al noted that tumor parameters, such as tumor differentiation, tumor depth, pattern of invasion, and perineural spread, were not important prognostic factors for local recurrence in surgically treated early oral cavity carcinomas when clear margins were obtained.¹² Despite the variability noted for some prognostic factors, the impact of clear surgical margins is well defined. Shingaki et al reported a 3% local recurrence rate in early-stage oral cavity carcinomas treated with negative margin surgery alone.13 Byers et al noted local recurrences in 80% of cases with positive margins in comparison to 20% in cases in which clear margins were obtained even if obtained by serial frozen sections.¹⁴

Patient Evaluation

Meticulous post-treatment surveillance is crucial in the care of patients with head and neck cancer. Variability in presentation exists among patients with recurrent oral cavity carcinomas. Most patients will experience pain and have obvious findings on physical examination. Some patients are asymptomatic but have obvious clinical findings of recurrence, and other patients will complain of pain without obvious clinical findings. By far the symptomatic patient without clinical findings is the most problematic for the head and neck oncologist.^15,16

Depending on the previous treatment given for the initial tumor, the clinical exam may be of limited value. This is especially true in cases that were initially treated with combined modality therapy and significant post-treatment fibrosis has developed. The use of a flap reconstruction can further complicate the evaluation, especially if a bulky flap was used. In these instances, imaging studies become critical in the evaluation to exclude recurrence. Typically, computed tomography (CT) and magnetic resonance imaging (MRI) are used to delineate postoperative changes from disease. In recent years, positron emission tomography (PET) using 2-fluoro-2-deoxy-D-glucose (FDG) has also become a useful tool in detecting post-treatment recurrence.

A multitude of characteristics can be evaluated on post-treatment CT scans to help determine the presence or absence of recurrent disease. Some would argue that the only reliable CT criteria to discriminate post-treatment change from tumor are stable masses or gradually decreasing masses on serial scans.¹⁷ Chikui et al reviewed CT scans on post-treatment oral cavity carcinomas to assess which radiographic findings were most predictive of recurrence.¹⁸ Enhancement was found to be a nonspecific finding before 6 months post-treatment. Not only was enhancement demonstrated in all the recurrent cases, but it was also noted in 60% of the cases that never demonstrated recurrence. After 6 months post-treatment, all patients with recurrences demonstrated enhancement, whereas only 20% of the cases that remained disease free were noted to have enhancement. The enhancement in these cases was classified as not suggestive of recurrence and eventually did resolve in one case. Similarly, low-density areas were present in a majority of recurrent cases but rarely noted in disease-free cases after 6 months post-treatment. Finally, adipose infiltration and adipose disappearance were almost exclusively noted in cases of recurrence.

The use of PET with FDG allows evaluation for tumor recurrence not by analysis of distorted anatomy, but by assessment of functionality of the tissue in question. In a prospective analysis, Anzai et al found a markedly improved diagnostic accuracy of PET over CT/MRI. In their cohort of 12 patients evaluated for recurrence, the sensitivity and specificity of PET versus CT/MRI were 88% and 100% versus 25% and 75%, respectively.¹⁹ Fischbein et al reported slightly different results in their study of 35 patients, with sensitivity and specificity for primary and nodal recurrences being 100%/64% and 93%/67%, respectively, using PET imaging.²⁰ The slight differences in results were attributed to slightly different guidelines used to determine a positive or negative scan. When compared with imaging with CT or MRI, PET was again noted to be much more reliable in the assessment of recurrence. As with CT/MRI, a period of time to allow for post-treatment changes to resolve must occur before imaging for recurrence. Greven et al noted that post-treatment PET scans for various head and neck cancers were unreliable at 1 month, but by 4 months they had a high positive predictive value and a negative predictive value of 100%.²¹

Staging of Recurrent Oral Cavity Carcinomas

The tumor, nodal, and metastases (TNM) staging system established by the American Joint Committee on Cancer (AJCC) is routinely applied to new oral cavity carcinomas. Staging of tumors has many benefits, including planning treatment, discussing prognosis, exchanging information between treating physicians, and stratifying patients for research purposes. Unfortunately, this system has limitations when applied to recurrent oral cavity carcinomas, especially after previous surgical therapy.^22,23 Specifically, some primary (T) staging is not possible after previous resections, and regional status (N) is not accurately reportable after previous neck dissections. Other patient factors not directly linked to the tumor’s anatomical extent, which may play a role in overall survival, are also not taken into account with the TNM staging system.^23,24 Because of these shortcomings, other staging systems have been developed in an attempt to better stratify patients with recurrent carcinomas.

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