**Oral Squamous Cell Carcinoma in Young Population — Risk Factors, Clinical Presentation, and Prognosis**

Ligia Buloto Schmitd, Kellen Cristine Tjioe, Agnes Assao and Denise Tostes Oliveira

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60712

## **1. Introduction**

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[304] Reis PP, Waldron L, Perez-Ordonez B, Pintilie M, Galloni NN, Xuan Y, Cervigne NK, Warner GC, Makitie AA, Simpson C *et al*: A gene signature in histologically normal surgical margins is predictive of oral carcinoma recurrence. *BMC cancer* 2011, 11:437.

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130 Contemporary Issues in Head and Neck Cancer Management

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The oral squamous cell carcinoma is a particular type of cancer classically described as a tobacco- and alcohol-related disease affecting mostly elderly male patients. However, epide‐ miologic studies have demonstrated an increasing incidence of young individuals with oral cancer. Interestingly, the clinicopathological profile, etiology, risk factors, and outcome of patients with early-onset disease seem to present several differences compared to late-onset oral carcinoma and these discrepancies are discussed below.

## **2. Clinical manifestations**

Retrospective studies including elderly and young patients have shown that the incidence of squamous cell carcinoma (SCC) of the mouth in young people is low but presents an increasing tendency [1]. In fact, there is certain heterogeneity of the cutoff age employed in the studies. Most authors consider young patients as those who are under 40 or 45 years [2-6] whereas few investigations select individuals under 20 or 30 years [7-9]. The incidence of oral cancer in patients younger than 40 years of age varies between 0.4–3.6%, but it can reach 6.7% in studies considering 45 years as the cutoff point [10]. Due to its rarity, most investigations deal with a small sample of patients, and conflicting results have been published regarding the epide‐ miological aspects of oral SCC.

The clear male predominance found in late-onset lesions is not found in the early-onset counterparts. Men are still more affected than women but only slightly more, with a F:M ratio

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varying from 1:1.2 to 1:4.9 [11, 12]. These data show an evident augmentation in the number of young women affected by oral SCC. The differences between sex distribution previously observed may be due to smoking and drinking habits, which are more socially acceptable for both genders currently [10].

The most common oral subsite for SCC in young patients is the tongue, with 39–77% of the cases [13, 14]. A study conducted in Taiwan found a higher incidence of oral SCC in the buccal area (53.6%) in comparison with the tongue (42, 8%), but betel chewing was common among these patients [15]. Other retrospective reports in Germany and Brazil showed a slightly higher incidence of oral SCC in the floor of the mouth, followed by the mobile tongue [12, 16].

The typical clinical appearance of oral SCC in young patients is an ulcer, often intermixed with white plaque and/or reddish areas. Kuriakose *et al.* [17] noted that lesions in young patients were predominantly invasive as compared with the exophytic lesions found in older patients [10, 17]. On the other hand, Falaki *et al.* [18] reported exophytic lesion with ulcer as the most common clinical presentation in younger individuals.

Figures 1 and 2 illustrate a 35-year-old young man who presented with a white plaque intermixed with erythroplastic areas in the right border of the tongue. The duration of the lesion was of one year, and the patient reported slight pain. Moreover, the individual did neither consume tobacco nor alcohol. Incisional biopsy confirmed the diagnosis of SCC that was staged lately as T2N0M0. The patient was submitted to partial glossectomy with supra‐ omohyoid selective neck dissection of the same side and radiotherapy. The one-year followup was uneventful.

**Figure 1.** Clinical features of oral SCC in young patient – presence of white plaque and ulceration at the right lateral surface of the mobile tongue of a 35-year-old patient.

Oral Squamous Cell Carcinoma in Young Population — Risk Factors, Clinical Presentation, and Prognosis http://dx.doi.org/10.5772/60712 133

Figure 1: Clinical features of oral SCC in young patient – presence of white plaque and ulceration at the right lateral

Figure 2: Arrows indicate a slightly elevated and indurated border of the lesion showed in Figure 1, demonstrating the infiltrative characteristic of the tumor. Regarding the symptoms, initial local pain is uncommon [19]. Other signs and symptoms can be dysphagia, weight loss and otalgia (26.5%, 26.6% and 37.5%, respectively) [20], but they seem to be related to the size and anatomic location of the tumor. **Figure 2.** Arrows indicate the lesion showed in Figure 1. Elevated and indurated borders were confirmed by palpation, demonstrating the infiltrative growth of the tumor.

Regarding the symptoms, initial local pain is uncommon [19]. Other signs and symptoms can be dysphagia, weight loss and otalgia (26.5%, 26.6% and 37.5%, respectively) [20], but they seem to be related to the size and anatomic location of the tumor. The duration of the symptoms before diagnosis can vary, but reported data show that most of the patients had early stage disease at the moment of diagnosis, that is, from 52-95% of the patients presented with lesions graded as T1 or T2, usually without neck metastasis [13, 21]. Fang *et al.* [22] reported that 80% of patients younger than 40 years-old with oral SCC presented lesions staged as T1 or T2 and only one tumor with positive node metastasis, appearing to be weakly aggressive at diagnosis. However, the clinical result was poor, as 10 (66.7%) patients exhibited recurrence and five (33%) patients succumbed to the disease [22].

The delay before diagnosis is usually between few weeks and 10 months [23, 24].

## **3. Microscopic findings**

surface of the mobile tongue of a 35-year-old patient.

3

varying from 1:1.2 to 1:4.9 [11, 12]. These data show an evident augmentation in the number of young women affected by oral SCC. The differences between sex distribution previously observed may be due to smoking and drinking habits, which are more socially acceptable for

The most common oral subsite for SCC in young patients is the tongue, with 39–77% of the cases [13, 14]. A study conducted in Taiwan found a higher incidence of oral SCC in the buccal area (53.6%) in comparison with the tongue (42, 8%), but betel chewing was common among these patients [15]. Other retrospective reports in Germany and Brazil showed a slightly higher incidence of oral SCC in the floor of the mouth, followed by the mobile tongue [12, 16].

The typical clinical appearance of oral SCC in young patients is an ulcer, often intermixed with white plaque and/or reddish areas. Kuriakose *et al.* [17] noted that lesions in young patients were predominantly invasive as compared with the exophytic lesions found in older patients [10, 17]. On the other hand, Falaki *et al.* [18] reported exophytic lesion with ulcer as the most

Figures 1 and 2 illustrate a 35-year-old young man who presented with a white plaque intermixed with erythroplastic areas in the right border of the tongue. The duration of the lesion was of one year, and the patient reported slight pain. Moreover, the individual did neither consume tobacco nor alcohol. Incisional biopsy confirmed the diagnosis of SCC that was staged lately as T2N0M0. The patient was submitted to partial glossectomy with supra‐ omohyoid selective neck dissection of the same side and radiotherapy. The one-year follow-

**Figure 1.** Clinical features of oral SCC in young patient – presence of white plaque and ulceration at the right lateral

both genders currently [10].

132 Contemporary Issues in Head and Neck Cancer Management

up was uneventful.

surface of the mobile tongue of a 35-year-old patient.

common clinical presentation in younger individuals.

The microscopic features that define an oral SCC do not differ between young and old patients. SCC is an invasive epithelial neoplasm with varying degrees of squamous differentiation. Disorganized stratified squamous epithelium forming strands and islands of bizarre epithelial cells presenting severe dysplasia infiltrating subjacent submucosa is observed. Dyskeratosis, polymorphism, hyperchromatism, atypical mitosis and loss of nucleolus-nucleus and nucleuscytoplasm ratio are also marked cellular characteristics [25], as shown in Figures 3 and 4.

The tumors are traditionally graded into well, moderately, and poorly differentiated SCC. According to the World Health Organization (WHO), well-differentiated carcinoma resembles closely normal squamous epithelium. Moderately differentiated carcinoma contains distinct nuclear pleomorphism and mitotic activity, including abnormal mitosis, and there is normally less keratinization. In poorly differentiated carcinoma, immature cells predominate, with numerous typical and atypical mitosis, and minimal keratinization. Most of the SCCs are moderately differentiated [25]. The studies in young population also showed a higher incidence of moderately differentiated oral tumors, ranging from 40.9% to 70% of the sample [7, 20, 26-29]. Hilly *et al.* [8] and Garavello *et al.* [27] found worse prognosis and higher indexes of moderately and poor differentiated tumors in their sample. Controversially, Hyam *et al.* [30] found similar prognosis associated with 67% of poorly differentiated tumors. Grading by differentiation is of limited prognostic value, as compared to the pattern of invasion [25].

**Figure 3.** Neoplastic squamous epithelium infiltrating subjacent submucosa (H&E original magnification X50).

**Figure 4.** Detail of neoplastic epithelial cells with atypical mitotic figures, dyskeratosis, and loss of nucleolus-nucleus and nucleus-cytoplasm ratio; neoplastic cells presenting polymorphism and hyperchromatism (H&E original magnifi‐ cation X400).

## **4. Etiology/risk factors**

## **4.1. Tobacco and alcohol**

less keratinization. In poorly differentiated carcinoma, immature cells predominate, with numerous typical and atypical mitosis, and minimal keratinization. Most of the SCCs are moderately differentiated [25]. The studies in young population also showed a higher incidence of moderately differentiated oral tumors, ranging from 40.9% to 70% of the sample [7, 20, 26-29]. Hilly *et al.* [8] and Garavello *et al.* [27] found worse prognosis and higher indexes of moderately and poor differentiated tumors in their sample. Controversially, Hyam *et al.* [30] found similar prognosis associated with 67% of poorly differentiated tumors. Grading by differentiation is of limited prognostic value, as compared to the pattern of invasion [25].

134 Contemporary Issues in Head and Neck Cancer Management

**Figure 3.** Neoplastic squamous epithelium infiltrating subjacent submucosa (H&E original magnification X50).

**Figure 4.** Detail of neoplastic epithelial cells with atypical mitotic figures, dyskeratosis, and loss of nucleolus-nucleus and nucleus-cytoplasm ratio; neoplastic cells presenting polymorphism and hyperchromatism (H&E original magnifi‐

cation X400).

In recent years, an increasing number of young patients, who declare to never having smoked or consumed alcohol excessively, are diagnosed with oral SCC [17, 31]. Tobacco smoke and alcohol abuse are considered well-established risk factors for oral SCC in older population. Otherwise, in young patients, these classical risk factors cannot be considered as the major ones for oral cancer [10, 17, 32, 33], if the period of abuse is not enough to create carcinogenesis [10].

On the other side, some studies report that tobacco use starts during adolescence [10], usually before 16 years old, making probable that before the age of 40 years, patients have an accumulated risk of more than 21 years of consumption, being more susceptible for the oral cancer [34].

Probably, the pathogenesis of oral SCC in young people involves multiple factors, as genetic and others new behavioral factors [32, 33]. It seems that tobacco and alcohol consumption are not the main etiological factors for oral SCC in young patients.

#### **4.2. Genetic factors**

Genetic predisposition for cancer development at young age, especially in those patients with no recognized risk factors seems to be preponderant [34]. Chromosome fragility, DNA ploidy abnormalities and increased familial risk of head and neck SCC have already been reported in young patients [26, 34, 35].

Considering the familial risk, a clear significant relative risk of SCC exists in first-degree family members of those who suffered head and neck cancer [35], especially when there is no recognized risk factor associated. Oral cancer has been associated with higher chromosome fragility and instability in youngsters, compared to elderly [36].

Genetic instability is an important molecular mechanism for head and neck cancers [35]. Gain and loss of specific chromosome regions in DNA are responsible for head and neck cancers, for example the 3p or 9p21 region, which are early events strictly related with head and neck cancer development, but that are not commonly seen in young people [35]. It is supposed that a completely different model of tumorigenesis exists, at a molecular level, in young people.

One essential step for tumorigenesis is deregulation of normal cell cycle regulatory system, especially in genes that control G1 to 2 phase progression in cell cycle [37]. The amplification of the gene CCDN1 was noted to be more expressive in young people [31]. CCDN1 is a protooncogene that encodes cyclin D1, a key regulator of G1 phase in cell cycle. The overexpression of cyclin D1 was found to be more prominent in young people [31], and it was correlated with disease-free survival in younger and elderly patients. Instead of these findings, larger studies are required to confirm the prognostic value of CCDN1 in young patients.

## **4.3. Behavioral and other factors**

#### *4.3.1. Marijuana consumption*

Several cases reported in the literature [38, 39] suggest an association between marijuana smoking and head and neck cancers and respiratory cancers, but this correlation is not conclusive.

The use of marijuana has been speculated as a risk factor for oral cancer in young people [10]. The main reason is that marijuana smoke contains carcinogens similar to those in tobacco, and marijuana smoking involves greater inhalation and longer retention of marijuana smoke [34]. However, the potential of carcinogenicity of tetrahydrocannabiol (THC), the major psychoac‐ tive ingredient in marijuana, is not clear yet [40], but it is evident that cannabinoids have an effect in tumorigenic or antitumorigenic role [41]. The patient with oral SCC illustrated in the Figures 1 and 2 confirmed frequent marijuana use when he was a teenager.

## *4.3.2. Immunodeficiencies*

Some chronic immunodeficiency states (Bloom syndrome, Wiskott-Aldrich syndrome), or even immunosuppression regimes following organ transplantation [34] and anemia (Patterson Kelly/ Plummer Vinson syndrome, Fanconi anemia) [35], might play important roles in carcinogenesis in young people. Specifically, Fanconi anemia has an associated higher risk for developing head and neck cancer, estimated to be 40% by the fourth to sixth decade of life. Mutations in telomerase complex are responsible for Fanconi anemia and regarding its malignant transformation, telomeres are repeatedly shortened precipitating a genetic insta‐ bility, allowing the progression to a malignant neoplasia [35].

Another distinct group that compound young head and neck cancer patients is those with cancer during childhood. The probability of a second synchronous tumor or metachronous primary tumor is estimated in 3–12% in 20 years of survival. Also, chemotherapeutic drugs and radiation can induce malignancies as side effects [7, 42].

#### *4.3.3. Diet*

A well-defined concept is that a diet rich in fruits and vegetables, with antioxidant properties, has a protective role against oral cancer [43]. A significant reduction in the risk of oral SCC was found among females consuming three or more portions of fresh fruits and vegetables daily [43, 44]. However, this factor is preponderant for the population in general and there are no studies on specific dietary behavior for young people.

#### *4.3.4. Viral infections*

The human papillomavirus (HPV) comprises a huge group of more than 50 subtypes of viruses able to infect the anogenital region and can be divided into two major subgroups: low-risk and high-risk types for cancer [45]. The low-risk HPVs are usually responsible for genital warts that rarely progress into malignancy whereas the high-risk ones have oncogenic capability, leading to the development of cancer. The HPV-16 and HPV-18 are the major high-risk types that are present in anogenital and head and neck cancers [45].

**4.3. Behavioral and other factors**

136 Contemporary Issues in Head and Neck Cancer Management

Several cases reported in the literature [38, 39] suggest an association between marijuana smoking and head and neck cancers and respiratory cancers, but this correlation is not

The use of marijuana has been speculated as a risk factor for oral cancer in young people [10]. The main reason is that marijuana smoke contains carcinogens similar to those in tobacco, and marijuana smoking involves greater inhalation and longer retention of marijuana smoke [34]. However, the potential of carcinogenicity of tetrahydrocannabiol (THC), the major psychoac‐ tive ingredient in marijuana, is not clear yet [40], but it is evident that cannabinoids have an effect in tumorigenic or antitumorigenic role [41]. The patient with oral SCC illustrated in the

Some chronic immunodeficiency states (Bloom syndrome, Wiskott-Aldrich syndrome), or even immunosuppression regimes following organ transplantation [34] and anemia (Patterson Kelly/ Plummer Vinson syndrome, Fanconi anemia) [35], might play important roles in carcinogenesis in young people. Specifically, Fanconi anemia has an associated higher risk for developing head and neck cancer, estimated to be 40% by the fourth to sixth decade of life. Mutations in telomerase complex are responsible for Fanconi anemia and regarding its malignant transformation, telomeres are repeatedly shortened precipitating a genetic insta‐

Another distinct group that compound young head and neck cancer patients is those with cancer during childhood. The probability of a second synchronous tumor or metachronous primary tumor is estimated in 3–12% in 20 years of survival. Also, chemotherapeutic drugs

A well-defined concept is that a diet rich in fruits and vegetables, with antioxidant properties, has a protective role against oral cancer [43]. A significant reduction in the risk of oral SCC was found among females consuming three or more portions of fresh fruits and vegetables daily [43, 44]. However, this factor is preponderant for the population in general and there are

The human papillomavirus (HPV) comprises a huge group of more than 50 subtypes of viruses able to infect the anogenital region and can be divided into two major subgroups: low-risk and high-risk types for cancer [45]. The low-risk HPVs are usually responsible for genital warts

Figures 1 and 2 confirmed frequent marijuana use when he was a teenager.

bility, allowing the progression to a malignant neoplasia [35].

and radiation can induce malignancies as side effects [7, 42].

no studies on specific dietary behavior for young people.

*4.3.1. Marijuana consumption*

*4.3.2. Immunodeficiencies*

conclusive.

*4.3.3. Diet*

*4.3.4. Viral infections*

Recent changes in the epidemiological profile of oral carcinoma have encouraged the research for new risk factors related to the development of oral cancer. For example, there has been a decrease in the tobacco-associated oral cancer and an increase of non-smoking white female young patients (18–44 years) who presented with oral SCC [46]. These facts, associated with the established oncogenic power of HPV-16 in cervix carcinoma [47] raised the hypothesis that HPV could be an etiological factor for oral SCC. Moreover, oral mucosa is highly exposed to chemical carcinogens, infections, and trauma, making it more vulnerable to carcinogenesis. Then, it has been postulated that abrasions caused due to this continuous exposure might make this mucosal surface more susceptible to HPV by making it easier for the virus to gain entry into the basal cells of oral mucosa [45].

The mechanism by which the high-risk HPVs promote the carcinogenesis has been already revealed. Once the cell is infected with HPV, the viral oncoproteins E6 and E7 are integrated to the cell genome and their expressions alter the host genome functions [45, 46]. HPV E6 and E7 proteins disrupt p53 and pRb tumor suppressor genes as well as numerous cellular proteins involved in carcinogenesis (BAK, telomerase, INK4A, E2F, cyclins A and E, WAF1, and KIP1) [46]. These accumulated defects in the genomic expression of the infected cells lead to cell immortalization and genomic instability by deactivation of control and regulatory mecha‐ nisms of cell apoptosis, cell cycle, and DNA repair [45, 46]. These mechanisms are essential for the development of cervix carcinoma, once HPV prevalence in this type of cancer is 100% [48]. The same is true for oropharyngeal SCC, with a HPV prevalence up to 90% [49, 50]. In oral SCC, the role of HPV still remains unclear. The anatomical structures of oropharynx, especially the base of the tongue and tonsils, seem to be more susceptible to HPV infection when compared to oral sites [34].

The prevalence of HPV in oral cancer may vary from 0 to 100% [51] and this may not be only due to ethno-geographical differences but to the sensitivity of the applied diagnostic technique and to the site of the lesion [51]. The first issue to study the HPV prevalence in these lesions is the techniques employed to detect it. The most accurate ones seem to be the polymerase chain reaction for the HPV DNA and *in situ* hybridization. The immunohistochemistry is also employed but it can lose its accuracy in old specimens [52].

In well-designed studies selected in an elegant review of the literature on the role of HPV in oral SCC, only nine split the groups between young and older people [5, 19, 53-59]. The presence of high-risk HPV had a negative impact for the patient's survival in four studies [5, 19, 55, 58], was neutral in three [53, 54, 59], and had a positive impact in only one investigation [57]. Putting together all data, there is a clear need of more studies with larger samples and more standardized methodology for the virus detection. Despite of the proved role of HPV in the carcinogenesis of the cervix and oropharynx, it is still difficult to draw any conclusion regarding the role of the high-risk HPV types 16 and 18 in the oral cancer development.

## **5. Treatment**

Most cases of oral SCC in young population occur at the mobile tongue. Treatment of tongue tumors at any age depends on the clinical stage at diagnosis. Surgery and radiotherapy are the standards of care for early-stage and also for locally advanced tumors in the oral cavity. The specific treatment is dictated by the TN stage and, if N0 at diagnosis, by the risk of nodal involvement [60]. For T1N0 tumors, surgical resection is recommended and no adjuvant therapy is necessary. The T2 to T4 N0 tumors require local surgery and supraomohyoid neck dissection. Treatment of the neck is expanded according to the worsening of cervical clinical staging. Postoperative radiotherapy is indicated in the following cases: clinical stage III or IV, presence of compromised or small surgical margins, presence of vascular or perineural infiltration, presence of lymph node involvement or extracapsular spread [61]. At present, there is no recommendation for a different approach on oral tumors in young patients [60].

Kaminagakura *et al.* [62] described a better overall survival in a group of young patients (<40 year-old) treated after 1991, when compared to similar patients treated earlier. They attributed this finding to the more aggressive and adequate treatment approaches applied and also to an early diagnosis. So, does the treatment of oral SCC of young people need to be more aggressive? This question can be answered only after understanding the evolution and prognosis of this disease affecting young people. There is a suggestion that people under the age of 40 should be treated differently from the older ones. This is based on the finding of high recurrence and low survival rates between the young. [27]. Also, aggressive therapeutic approach for tongue cancer was recommended by Myers *et al.* [20], with no age distinction. Controversially, Goepfert *et al.* [6] described that young women (<45 years) with oral SCC had similar prognosis when compared to older men and women with this disease, highlighting the unnecessary adoption of adjuvant therapies in this particular group. Is it time to rethink the aggressive treatments and the use of adjuvant unnecessary therapies [21]?

When over treatment occurs in young people, it may be motivated by emotional aspects involving the diagnosis of a lethal condition in such a young person. Also, a radical option may be influenced by the surgeon's experience rather than by scientific evidence [6]. So, it is of utmost importance to know if these tumors have worse prognosis to justify a more aggres‐ sive therapy.

#### **6. Prognosis**

The outcome for oral SCC occurring in youngsters is a major controversial issue. Various studies have attempted to elucidate the prognostic significance of patient age at diagnosis. Unfortunately, there are no prospective studies comparing elderly and younger patients regarding prognosis. Also, there is no large multicentric research on this topic.

An ordinary question that can greatly affect the results of prognostic studies is the very definition of what would be a young patient with oral SCC. This age limit is empirical and most studies use 40-year-old as the cutoff age [2, 4, 27, 29, 30, 63, 64]. Some outcome analyses use the age of 30, 35, 45 [3, 5-8, 15, 28, 66] or even 60 years as the limit to be considered young [67]. Pediatric patients with oral tumors (under 20 years) have also been studied [9]. So, if there is not much consensus on the age of the patients to be considered young, it is quite difficult to achieve consistent results, regarding the prognosis, when comparing these studies.

**5. Treatment**

138 Contemporary Issues in Head and Neck Cancer Management

sive therapy.

**6. Prognosis**

Most cases of oral SCC in young population occur at the mobile tongue. Treatment of tongue tumors at any age depends on the clinical stage at diagnosis. Surgery and radiotherapy are the standards of care for early-stage and also for locally advanced tumors in the oral cavity. The specific treatment is dictated by the TN stage and, if N0 at diagnosis, by the risk of nodal involvement [60]. For T1N0 tumors, surgical resection is recommended and no adjuvant therapy is necessary. The T2 to T4 N0 tumors require local surgery and supraomohyoid neck dissection. Treatment of the neck is expanded according to the worsening of cervical clinical staging. Postoperative radiotherapy is indicated in the following cases: clinical stage III or IV, presence of compromised or small surgical margins, presence of vascular or perineural infiltration, presence of lymph node involvement or extracapsular spread [61]. At present, there is no recommendation for a different approach on oral tumors in young patients [60].

Kaminagakura *et al.* [62] described a better overall survival in a group of young patients (<40 year-old) treated after 1991, when compared to similar patients treated earlier. They attributed this finding to the more aggressive and adequate treatment approaches applied and also to an early diagnosis. So, does the treatment of oral SCC of young people need to be more aggressive? This question can be answered only after understanding the evolution and prognosis of this disease affecting young people. There is a suggestion that people under the age of 40 should be treated differently from the older ones. This is based on the finding of high recurrence and low survival rates between the young. [27]. Also, aggressive therapeutic approach for tongue cancer was recommended by Myers *et al.* [20], with no age distinction. Controversially, Goepfert *et al.* [6] described that young women (<45 years) with oral SCC had similar prognosis when compared to older men and women with this disease, highlighting the unnecessary adoption of adjuvant therapies in this particular group. Is it time to rethink the aggressive

When over treatment occurs in young people, it may be motivated by emotional aspects involving the diagnosis of a lethal condition in such a young person. Also, a radical option may be influenced by the surgeon's experience rather than by scientific evidence [6]. So, it is of utmost importance to know if these tumors have worse prognosis to justify a more aggres‐

The outcome for oral SCC occurring in youngsters is a major controversial issue. Various studies have attempted to elucidate the prognostic significance of patient age at diagnosis. Unfortunately, there are no prospective studies comparing elderly and younger patients

An ordinary question that can greatly affect the results of prognostic studies is the very definition of what would be a young patient with oral SCC. This age limit is empirical and

regarding prognosis. Also, there is no large multicentric research on this topic.

treatments and the use of adjuvant unnecessary therapies [21]?

Some retrospective reports attempted to analyze prognosis for young population with oral SCC, but they did not compare this data to older counterparts [20, 21, 23, 24, 68-76]. Mallet *et al.* [68] found a high rate of persistent evolution and tumor recurrence within the first year after treatment in a group of patients under 35-year-old, and this affected negatively the overall survival. McGregor *et al.* [24] reported 80% cure rate among patients less than 40 years, but similarly to Mallet *et al.* [68], patients who died from disease usually had a poor response to initial treatment (within the first 2 years). Exceptionally good overall survival for patients < 40 years had been reported [20, 69]*.* These results suggest a good survival for young patients, albeit with a subgroup of patients developing short term recurrence. The lack of comparison with older counterparts weakened the results, regarding the role of age in prognosis.

The first comparative studies of oral SCC in young and old patients were published in 1998 by Siegelman-Danielli *et al.* [28] and Friedlander *et al.* [2]. They found similar outcome between the groups. Subsequently, another 16 reports compared the evolution of young and older patients with oral SCC, only 4 of them reporting worse prognosis. Analyzing these results, it appears that age at diagnosis has no significance in the outcome for oral SCC.

A matched-pair analysis methodology was performed by some of these comparative reports [2, 3, 5, 6, 15, 27, 62]. This design aims to match similar patients from 2 different groups (old and young), often by sex and disease stage. So, when matched pairs are analyzed, the matched variables are controlled, highlighting the patient's age as an outcome predictor. Only one matched pair analysis [27] showed worse prognosis for young oral cancer patients. This literature is summarized on Table 1.

Although many authors recognized that early age at diagnosis is not an individual factor that worsened outcome, some important information can be extracted from their results. In general, more young patients have recurred locally and regionally [2, 4, 6, 22, 27, 29, 30, 62-64, 65]. This finding may be explained by two theories: lack of adequate treatment and biologically different behavior. Fang *et al*. [22] found 60% of local recurrence in young patients versus 11% among the older ones, and both groups were treated similarly. Another study observed that most of the recurrent young patients had been initially treated with radiotherapy and that this could be the cause for the high recurrence rate [4]. In fact, the reason for inadequate treatment could be explained by the intention to cause less morbidity because of the lower age. Aggressiveness of the surgical procedure is difficult to compare, mainly because it suffers influence of subjective factors during the surgical act and most of the studies had no information about the margin size and status. However, because of the similar treatment approaches used in young and old patients in most of the reports, it is possible that these tumors have a unique biological behavior that needs to be well understood. Siegelmann-Danieli *et al.* [28] reported that tumors developed in the absence of tobacco or alcohol occurred more frequently in young patients and that patients at any age who developed disease without these risk factors may have a worse outcome, reinforcing different pathological behavior.


**Table 1.** Literature review of comparative studies evaluating younger age as a predictor of outcome in oral SCC.

Another interesting fact is that young patients recurred earlier [3, 64] and a high percentage of these recurrent young patients died of their disease [2, 3, 8, 22, 27]. A high index of recurrent disease associated with fatality was observed in the reports of Friedlander *et al.* [2] and Hilly *et al.* [8] (90% and 100%, respectively) and early fatality in 40% was reported by Popovtzer *et al.* [3] (within the two first years).

Moreover, there is some evidence that young patients developed more distant metastasis than the older counterparts [7, 66]. No strong known predicting factors for distant metastasis was found [65] and the observation of 100% incidence of death in distant failure patients indicated that young patients more often present with more advanced disease and may have a distinct pattern of recurrence [7]. Controversially, Fang *et al.* [22] observed 66% of locoregional recurrence without a single distant metastasis in a group of young patients (n=15).

**Authors Year Country Cases/controls Age limit\* Study Design Outcome**

**Pitman et al.** 2000 USA 122/150 40 Non-matched Similar

**Hyam et al.** 2003 Australia 15/48/60 40 Non-matched Similar **Veness et al.** 2003 Australia 22/142 40 Non-matched Similar

**Liao et al.** 2006 Taiwan 76/220 40 Non-matched Similar

analysis

analysis

analysis

analysis

analysis

analysis

analysis

Similar

Worse (women)

Similar

Similar/ Undefined

Better

Worse

Better

Similar

Worse when recurrent

Similar

**Siegelmann-Danieli et al.** 1998 USA 30/57 45 Non-matched Similar

**Fredlander et al.** <sup>1998</sup> USA 36/36 <sup>40</sup> Matched-pair

140 Contemporary Issues in Head and Neck Cancer Management

**Vargas et al.** 2000 USA 17/17 40 Non-matched

**Popovtzer et al.** <sup>2004</sup> Israel 16/32 <sup>45</sup> Matched-pair

**Siriwardena et al.** 2007 Sri Lanka 56/56 40 Non-matched

**Lee et al.** <sup>2007</sup> Taiwan 20/20 <sup>45</sup> Matched-pair

**Garavelo et al.** <sup>2007</sup> Italy 46/92 <sup>40</sup> Matched-pair

**Ho et al.** <sup>2008</sup> Taiwan 28/56 <sup>45</sup> Matched-pair

**Kaminagakura et al.** <sup>2010</sup> Brazil 125/250 <sup>41</sup> Matched-pair

**Hilly et al.** 2013 Israel 16/62 30 Non-matched

**Goepfert et al.** <sup>2014</sup> USA 18/36 <sup>45</sup> Matched-pair

**Table 1.** Literature review of comparative studies evaluating younger age as a predictor of outcome in oral SCC.

Another interesting fact is that young patients recurred earlier [3, 64] and a high percentage of these recurrent young patients died of their disease [2, 3, 8, 22, 27]. A high index of recurrent disease associated with fatality was observed in the reports of Friedlander *et al.* [2] and Hilly *et al.* [8] (90% and 100%, respectively) and early fatality in 40% was reported by Popovtzer *et*

\*age limit for the young patient's group.

*al.* [3] (within the two first years).

**Morris et al.** 2010 USA 10/40 20 Non-matched Similar

**Park et al.** 2010 Korea 23/62 45 Non-matched Worse **Soudry et al.** 2010 Israel 11/74 30 Non-matched Similar

**Fang et al.** 2014 China 15/161 40 Non-matched Similar

Some recognized microscopic adverse risk features for oral SCC are the extracapsular nodal spread,positivemargins,perineuralinvasion,andvascularembolism[60].Unfortunately,there is lack of information on microscopic status of the tumors in many reports [3, 5, 9, 63, 64, 66]. Perineural invasion was found to be similar between groups of young and old patients [7, 8]. Siegelmann-Danieli *et al*.[28] found similar extracapsular involvement in both groups, while Hilly*et al.*[8]andSoudry*et al*.[7]foundhigher,butnot significant,indexof extracapsular spread in young patients with nodal disease. There is evidence that cellular differentiation, depth of tumor, nerve invasion and extracapsular spread of the involved lymph node were risk factors fordistantmetastasis inyoungpopulationwithoral cancer.However,these characteristicswere not exclusive for young patients [65]. Studies failed to correlate extracapsular involvement, differentiation and perineural invasion to worse outcome in the young [7, 8].

The correlation between the expression of Ki-67, cyclin D1, p16, PCNA, EGFR and angiogenesis with outcome was investigated in young oral cancer population [31, 58, 69, 77, 78]. Overex‐ pression of Ki-67, a cell proliferation marker, was similar in both young and old patients. Angiogenesis also had a similar rate [77]. Moreover, the high expression of cyclin D1 was an indicator of worsened prognosis in both young and old groups [31]. P16 was a marker of favorable prognosis among young population, although not a reliable predictor of HPV presence [58]. A significantly increased number of mitosis, accompanied by strong PCNA expression and higher number of metastasis in the older group were found by Siriwardena *et al*. [78]. The authors believe that oral SCC in the older group is more proliferative, compared with younger patients. Low levels of EGFR expression were associated with lower recurrence rate in young patients, and those with high levels of expression had adverse prognosis [69]. Although there are microscopic factors recognizably influencing prognosis, the available studies failed to demonstrate them in oral cancer affecting young population. These results may be partially explained by the small groups analyzed. The immunoprofile of these tumors are yet to be elucidated, and it appears to be a promising area of research.

A common limitation to all the comparative studies of oral cancer in young people is the small population analyzed, since SCC of the oral cavity is a rare tumor. The largest group of young patients in a single hospital was 125 people at Brazil, but unfortunately the high rates of T3 and T4 disease made this group quite different from the other ones [62]. Pitmann *et al.* [63] studied 122 cases, but their population was not uniform, since 94 of these patients were extracted from previous literature reports. The lower the cutoff age, the lower the sample size. Morris *et al.* [9] and Soudry *et al.* [7] studied only 10 patients (< 20 years) and 11 patients (< 20 years), respectively.

## **7. Conclusions**

Oral SCC in young people accounts for about 0.4–2.6% of the total incidence and has a slight predominance in men. The most common location for this tumor is the tongue and occurrence of symptoms is rare unless the lesion reaches a wide size. The delay before diagnosis varies from few weeks to approximately 10 months.

Concerning the etiological factors for oral SCC in young adults who do not smoke and drink alcohol frequently, genetic abnormalities seem to have a preponderant role in development of the tumor. Additionally, human papilloma virus infection, specifically by HPV-16 and HPV-18, are more frequently detected in this group, but more studies are needed to confirm its influence in prognosis and clinical outcome of oral SCC in the younger.

In the light of current knowledge, it is possible to affirm that age is not an independent outcome predictor for oral SCC. However, a group of young patients that develops a more aggressive disease with a recurrent pattern seems to exist. In this group, early death is common. It is not possible yet to point out the causes for this aggressive behavior. Supported by published studies, treatment should be aggressive for both younger and older patients, and there is no rationale for different approach in young population with oral SCC. Also, further multicentric studies with standardized treatment protocols are necessary in order to elucidate the contro‐ versies of this fatal and increasing disease.

## **Author details**

Ligia Buloto Schmitd1,2, Kellen Cristine Tjioe1 , Agnes Assao1 and Denise Tostes Oliveira1\*

\*Address all correspondence to: d.tostes@fob.usp.br

1 Department of Stomatology, Pathology Division, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil

2 Department of Stomatology, FAESA Dental School, Vitória, ES, Brazil

## **References**

[1] Patel SC, Carpenter WR, Tyree S, Couch ME, Weissler M, Hackman T, Hayes DN, Shores C, Chera BS. Increasing Incidence of Oral Tongue Squamous Cell Carcinoma in Young White Women, Age 18 to 44 Years. Journal of Clinical Oncology 2011; 29(11) 1488-1494.

[2] Friedlander PL, Schantz SP, Shaha AR, Yu G, Shah JP. Squamous Cell Carcinoma of the Tongue in Young Patients: a Matched-Pair Analysis. Head & Neck 1998; 20(5) 363-368.

**7. Conclusions**

from few weeks to approximately 10 months.

142 Contemporary Issues in Head and Neck Cancer Management

versies of this fatal and increasing disease.

Ligia Buloto Schmitd1,2, Kellen Cristine Tjioe1

\*Address all correspondence to: d.tostes@fob.usp.br

**Author details**

**References**

São Paulo, Bauru, SP, Brazil

29(11) 1488-1494.

Oral SCC in young people accounts for about 0.4–2.6% of the total incidence and has a slight predominance in men. The most common location for this tumor is the tongue and occurrence of symptoms is rare unless the lesion reaches a wide size. The delay before diagnosis varies

Concerning the etiological factors for oral SCC in young adults who do not smoke and drink alcohol frequently, genetic abnormalities seem to have a preponderant role in development of the tumor. Additionally, human papilloma virus infection, specifically by HPV-16 and HPV-18, are more frequently detected in this group, but more studies are needed to confirm

In the light of current knowledge, it is possible to affirm that age is not an independent outcome predictor for oral SCC. However, a group of young patients that develops a more aggressive disease with a recurrent pattern seems to exist. In this group, early death is common. It is not possible yet to point out the causes for this aggressive behavior. Supported by published studies, treatment should be aggressive for both younger and older patients, and there is no rationale for different approach in young population with oral SCC. Also, further multicentric studies with standardized treatment protocols are necessary in order to elucidate the contro‐

, Agnes Assao1

1 Department of Stomatology, Pathology Division, Bauru School of Dentistry, University of

[1] Patel SC, Carpenter WR, Tyree S, Couch ME, Weissler M, Hackman T, Hayes DN, Shores C, Chera BS. Increasing Incidence of Oral Tongue Squamous Cell Carcinoma in Young White Women, Age 18 to 44 Years. Journal of Clinical Oncology 2011;

2 Department of Stomatology, FAESA Dental School, Vitória, ES, Brazil

and Denise Tostes Oliveira1\*

its influence in prognosis and clinical outcome of oral SCC in the younger.


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## **Local Metastasis in Head and Neck Cancer - an Overview**

Suwarna Dangore–Khasbage

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60072

## **1. Introduction**

Head and neck cancer refers to epithelial malignancies of various parts of the orofacial region, which include paranasal sinuses, nasal cavity, pharynx and larynx, etc. These represent about 6% of all cancer cases and account for a number of new cancer cases and cancer-related deaths worldwide every year [1, 2]. Amongst those, oral cancer is the most common type of cancer. Squamous cell carcinoma is the most frequent single entity, constituting 95% of all oral malignancies [3].

Oral squamous cell carcinoma is an invasive lesion with the presence of perineural growth. It has a significant recurrence rate and frequently metastasizes to cervical lymph nodes. Since squamous cell carcinoma constitutes the preponderance of primary malignancies of the head and neck, it is by far the most common tumour that spreads to the cervical nodes [4]. Reports from the American Cancer Society indicate that, at the time of initial diagnosis, over 40% of patients with squamous cell carcinomas of the oral cavity and pharynx present with regional dissemination of the disease [5].

In oral cancer, tumour dissemination occurs via regional lymphatic to cervical lymph node in a predictable and sequential fashion. Oral cancer occurring in the posterior aspect of the oral cavity, oropharynx and inferior of the mouth tends to be associated with a higher incidence of spread to the lymph nodes at the time of diagnosis. Ipsilateral lymph nodes metastases are frequent. However, its spreading to contralateral nodes is more common with midline and posterior lesions [6].

The incidence of spread is influenced by the size of the tumour. Lesions classed as T1 may show a regional spread in 10 to 20% of cases, T2 lesions in 25 to 30% of cases and T3 to T4 tumours in 50 to 75% [6].

The determination of the presence or absence of metastases in the neck nodes is mandatory for cancer-bearing patients. This is because the therapeutic rational and prognosis depend on

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the staging of the cancer. It is stated that the presence of metastatic node reduces the 5-year survival rate by 50%. Moreover, the presence of another metastatic node on the contralateral side further reduces the survival rate by 25% [7]. Patients with metastasis need more aggressive treatments. Therefore, it is important to assess as reliably as possible whether or not a patient has regional lymph node metastases.

The common cause of metastatic cervical lymphadenopathy is the spread from primary tumours in the head and neck region. However, in unusual cases, they represent secondary tumours from primary sites below the clavicles [3]. The diagnosis of such cervical neck tumours can be decided after a complete clinical and radiological examination, focusing on the organs or areas where there is a high chance of an existing primary tumour.

## **2. Mechanism of metastases in head and neck cancer**

The most deadly aspect of any cancer is its ability to spread or metastasize. Metastasis is a complex process involving the detachment of cells from the tumour tissue, the regulation of cell motility and invasion, and the proliferation and evasion through the lymphatic system or blood vessels.

There are different views regarding the involvement of regional lymph nodes in metastasis. The nearby lymph nodes in tumour-bearing hosts are considered as anatomic barriers to the spread of tumour cells. On the contrary, another concept is that the lymphatic and lymphati‐ covenous shunts bypass the regional lymph nodes and allow both the lymphatic and haema‐ togenous dissemination of malignant cells. [8].

Cancer cells have the ability to overcome the safeguards that are present in the body for the prevention of metastasis. It is necessary to understand what ways cancer cells have mutated in order to circumvent the body's defences and travel freely to other locations.

#### **2.1. Lymphatic drainage in head and neck cancer**

Several important groups of lymph nodes act as first echelon nodes of the oral cavity. The first lymph node encountered in the channel, which drains a particular submucosal or subepider‐ mal lymph capillary plexus, is called the first echelon node. This is because it is here that pathogenic organisms or free tumour cells within the lymph fluid meet their first resistance to travel. A sentinel lymph node is defined as the first lymph node in a regional lymphatic basin that receives lymph flow from the primary tumour. Sentinel node imaging provides a "road map" of the lymphatic drainage from a tumour. However, it does not provide information regarding the presence or absence of cancer cells in those nodes.

Sometimes, lymphatic metastases do not first develop in the lymph nodes nearest to the tumour. This is known as skip metastases. The reason for this phenomenon could be venous lymphatic anastomoses or obliteration of lymphatics by inflammation or radiation. Due to the obstruction of the lymphatics by tumour cells, the lymph flow is disturbed and the tumour cells spread against the flow of the lymph. This causes retrograde metastases at unusual sites, for example, metastases of carcinoma prostrate to the supraclavicular nodes. It is believed that lymph nodes in the vicinity of the tumour perform multiple roles – first, acting as an initial barrier filter and destructing tumour cells, while later providing fertile soil for the growth of tumour cells [9].

Cervical lymph nodes include the submental, prevascular facial and submandibular group of lymph nodes. Deep jugular lymph nodes include the jugulodigastric, juguloomohyoid and supraclavicular group of lymph nodes. Lymph nodes in the posterior triangle of the neck include the accessory chain of lymph nodes. The mucosa of the upper aerodigestive tract drains to the cervical lymph nodes in the lateral aspect of the neck. Tumours of the pharynx may drain to the parapharyngeal and retropharyngeal lymph nodes.

The Delphian lymph node is present in the central compartment of the neck and drains the larynx and perithyroid lymph nodes adjacent to the thyroid gland. Lymph nodes in the tracheoesophageal groove provide primary drainage to the thyroid gland, as well as the hypopharynx, subglottic larynx and cervical oesophagus. Lymph nodes in the anterior superior mediastinum provide drainage to the thyroid gland and the oesophagus. Further‐ more, they serve as a secondary lymphatic basin for anatomic structures in the central compartment of the neck. Each anatomic subgroup of lymph nodes described above specifi‐ cally serve as primary echelon lymph nodes, draining a specific site in the head and neck region. Thus, the location of a palpable metastatic lymph node may often indicate the source of a primary tumour [8].

### **2.2. Assumptions about the mechanism of metastases**

the staging of the cancer. It is stated that the presence of metastatic node reduces the 5-year survival rate by 50%. Moreover, the presence of another metastatic node on the contralateral side further reduces the survival rate by 25% [7]. Patients with metastasis need more aggressive treatments. Therefore, it is important to assess as reliably as possible whether or not a patient

The common cause of metastatic cervical lymphadenopathy is the spread from primary tumours in the head and neck region. However, in unusual cases, they represent secondary tumours from primary sites below the clavicles [3]. The diagnosis of such cervical neck tumours can be decided after a complete clinical and radiological examination, focusing on the organs

The most deadly aspect of any cancer is its ability to spread or metastasize. Metastasis is a complex process involving the detachment of cells from the tumour tissue, the regulation of cell motility and invasion, and the proliferation and evasion through the lymphatic system or

There are different views regarding the involvement of regional lymph nodes in metastasis. The nearby lymph nodes in tumour-bearing hosts are considered as anatomic barriers to the spread of tumour cells. On the contrary, another concept is that the lymphatic and lymphati‐ covenous shunts bypass the regional lymph nodes and allow both the lymphatic and haema‐

Cancer cells have the ability to overcome the safeguards that are present in the body for the prevention of metastasis. It is necessary to understand what ways cancer cells have mutated

Several important groups of lymph nodes act as first echelon nodes of the oral cavity. The first lymph node encountered in the channel, which drains a particular submucosal or subepider‐ mal lymph capillary plexus, is called the first echelon node. This is because it is here that pathogenic organisms or free tumour cells within the lymph fluid meet their first resistance to travel. A sentinel lymph node is defined as the first lymph node in a regional lymphatic basin that receives lymph flow from the primary tumour. Sentinel node imaging provides a "road map" of the lymphatic drainage from a tumour. However, it does not provide information

Sometimes, lymphatic metastases do not first develop in the lymph nodes nearest to the tumour. This is known as skip metastases. The reason for this phenomenon could be venous lymphatic anastomoses or obliteration of lymphatics by inflammation or radiation. Due to the obstruction of the lymphatics by tumour cells, the lymph flow is disturbed and the tumour cells spread against the flow of the lymph. This causes retrograde metastases at unusual sites,

in order to circumvent the body's defences and travel freely to other locations.

or areas where there is a high chance of an existing primary tumour.

**2. Mechanism of metastases in head and neck cancer**

togenous dissemination of malignant cells. [8].

**2.1. Lymphatic drainage in head and neck cancer**

regarding the presence or absence of cancer cells in those nodes.

has regional lymph node metastases.

152 Contemporary Issues in Head and Neck Cancer Management

blood vessels.

Lymph node metastasis occurs by haematogenous or by lymphatic routes. The cancer mass has the same vascularity as that of healthy tissue. Thus, the cancer cells have access to the blood stream. The malignant cells are detached from the tumour mass and enter the body's circula‐ tion. Once in the bloodstream, the cancer cells circulate to other parts of the body. Similarly, the lymphatic system has channels throughout the body, like the circulatory system, through which a malignant cell can travel and metastasize.

If the cells travel through the lymph system, they may end up in nearby lymph nodes or spread to other organs. In circulation, the cancer cells may reach to any part of the body where they begin to grow and form a secondary tumour mass. This spread of cancer to a new part of the body is called metastasis. The spread of malignancy to nearby lymph nodes is called local or regional metastasis and the spread of the tumour to a distant organ is called a distant meta‐ stasis.

Cancer cells have to go through several steps in order to spread to new parts of the body:


There are various factors that may influence the mechanism of regional metastases and prevent tumour cells from developing lymph node metastases. These are:


Reviews of literature recommend that there are multiple and diverse reasons for cervical lymph node metastases in head and neck cancer. However, by any means, the careful evalu‐ ation of these metastatic regional nodes is essential for appropriate treatment and to achieve the best outcome of the treatment. Certainly, a careful clinical examination must be carried out at the beginning of the journey regarding the evaluation of the status of cervical lymph nodes in head and neck cancer.

## **3. Clinical examination of lymph nodes in head and neck cancer**

Customarily, all of the palpable cervical lymph nodes are considered as positive for regional metastasis in oral cancer. Thus, to treat all necks by considering the significant risk of having occult lymph node metastases is a traditional approach for the treatment of oral cancer. However, this approach often involves the unnecessary treatment of necks that ultimately prove to be pathologically free of cancer. Therefore, appropriate investigations should be carried out. These will help to determine the treatment plan, prognosis and morbidity by diminishing the possibility of unnecessary neck dissection.

The location, number, size, shape, tenderness, consistency and fixity to underlying structures are the criteria routinely used during a clinical examination of the cervical lymph nodes.

Usually, a 1 cm size cut-off in the largest axial diameter is used for metastatic disease. However, size is not a reliable marker of malignancy as small nodes can harbour small metastases that do not expand the node and conversely, benign nodes can be enlarged due to hyperplasia or inflammation. Thus, the nodes of less than 1 cm should also be carefully evaluated, particularly if they are in expected drainage sites of the primary tumour. In clinical practice, the size of the lymph node is only considered useful when there is an increase in nodal size on serial examinations in a patient with a known primary tumour, which is highly suggestive of metastasis.

**d.** They need to survive in a blood vessel or lymph vessel and move through it into a new

**f.** They need to be able to multiply and grow to form secondary neoplasm at the new site.

There are various factors that may influence the mechanism of regional metastases and prevent

**2.** The microvascular invasion, grade of differentiation and tumour thickness in metastases

**3.** The lymphatic vessel in and around the tumour tissue and lymph node metastasis in patients with oral squamous cell carcinoma. The dimension of lymphatic vessels is significantly greater in the tumour tissue than in the tumour-free tissue. This means that the function of lymphatic vessels appear to have increased in the tumour tissue, compared

Reviews of literature recommend that there are multiple and diverse reasons for cervical lymph node metastases in head and neck cancer. However, by any means, the careful evalu‐ ation of these metastatic regional nodes is essential for appropriate treatment and to achieve the best outcome of the treatment. Certainly, a careful clinical examination must be carried out at the beginning of the journey regarding the evaluation of the status of cervical lymph nodes

Customarily, all of the palpable cervical lymph nodes are considered as positive for regional metastasis in oral cancer. Thus, to treat all necks by considering the significant risk of having occult lymph node metastases is a traditional approach for the treatment of oral cancer. However, this approach often involves the unnecessary treatment of necks that ultimately prove to be pathologically free of cancer. Therefore, appropriate investigations should be carried out. These will help to determine the treatment plan, prognosis and morbidity by

The location, number, size, shape, tenderness, consistency and fixity to underlying structures are the criteria routinely used during a clinical examination of the cervical lymph nodes.

Usually, a 1 cm size cut-off in the largest axial diameter is used for metastatic disease. However, size is not a reliable marker of malignancy as small nodes can harbour small metastases that do not expand the node and conversely, benign nodes can be enlarged due to hyperplasia or inflammation. Thus, the nodes of less than 1 cm should also be carefully evaluated, particularly

**e.** Malignant cells have to emerge from a blood or lymph vessel.

154 Contemporary Issues in Head and Neck Cancer Management

tumour cells from developing lymph node metastases. These are:

of squamous cell carcinoma of the oral cavity [10].

diminishing the possibility of unnecessary neck dissection.

**g.** They need to be able to avoid attacks from the body's immune system.

to the tumour-free tissue. This results in regional metastasis [11].

**3. Clinical examination of lymph nodes in head and neck cancer**

**1.** The suppression of cellular immune response, in particular T cell function [7].

organ.

in head and neck cancer.

Metastatic disease can change the shape of the node by infiltrating nodal tissue and expanding the nodal capsule. Rounded nodes are more suspicious than oval nodes. As the disease progresses, ill-defined irregular margins in a lymph node are a sign of malignancy and may represent an extracapsular spread of tumour.

Metastatic lymph nodes are usually painless and thus, remain undetected by the patient until they reach considerable dimensions. Characteristically, these nodes are stony-hard and freely movable until the tumour cells penetrate the node capsule and invade the surrounding tissue. Then, they become fixed and the expanding tumour may amalgamate surrounding nodes into one larger, stony-hard and fixed mass. Sometimes, the small tumours in the nasal cavities, nasopharynx and larynx may go undetected. The only evidence of their presence is the metastatic tumour.

Oral cavity tumours usually cause metastasis in the submandibular and upper cervical regions. Rarely, lymph nodes in the posterior triangle may also be involved. The malignancy of the tongue base and tonsillar fossa is often the reason for metastatic lymphadenopathy in the posterior triangle of neck.

**Figure 1.** Ulceroproliferative growth with rolled edges, involving buccal and lingual vestibule and alveolar ridge in a 62-year-old male. There was a history of tobacco-lime quid keeping in the same region since 30 years of age.

**Figure 2.** Showing an enlarged (4 × 4 cm), hard and fixed submandibular lymph node in a patient with a malignancy of bucco- lingual vestibule and alveolar ridge (extra oral photograph of the same 62-year-old male, shown in Figure 1)

## **4. Clinical staging of cervical lymph nodes in head and neck cancer**

In the 1940s, the tumour-node-metastasis (TNM) staging system was reported by Pierre Denoix. The TNM staging system is an anatomic staging system that describes the anatomic extent of the primary tumour, the involvement of regional lymph nodes and distant metastasis.

As head and neck cancers consist of tumours arising from a variety of anatomic sites, such as the oral cavity, nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, larynx, oesophagus, thyroid gland, salivary glands, etc., and miscellaneous tumours, such as neurogenic tumours, it is impossible to generate a uniform staging system that would be relevant for all tumours arising in the head and neck region. In current practice, information obtained from the clinical examination and radiologic imaging is used to assign a clinical stage (cTNM). This is then used to stratify patients for a selection of therapy and to report outcomes of the treatment.

For many decades, the AJCC-UICC TNM staging system has been used worldwide for staging head and neck cancer [12, 13]. This system has been periodically revised for improvement. According to this, the cervical lymph nodes are divided into seven levels or groups, which are based on the extent and level of cervical nodal involvement by metastatic tumour. Although this classification of cervical lymph nodes is commonly used, especially by surgeons and oncologists, some important lymph nodes, such as parotid and retropharyngeal nodes, are not included in this classification.


**Table 1.** N staging for all Head and neck sites except the nasopharynx and thyroid - AJCC/UICC 2002 [12, 13].


\*Midline nodes are considered ipsilateral nodes.

**Figure 2.** Showing an enlarged (4 × 4 cm), hard and fixed submandibular lymph node in a patient with a malignancy of bucco- lingual vestibule and alveolar ridge (extra oral photograph of the same 62-year-old male, shown in Figure 1)

In the 1940s, the tumour-node-metastasis (TNM) staging system was reported by Pierre Denoix. The TNM staging system is an anatomic staging system that describes the anatomic extent of the primary tumour, the involvement of regional lymph nodes and distant metastasis. As head and neck cancers consist of tumours arising from a variety of anatomic sites, such as the oral cavity, nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, larynx, oesophagus, thyroid gland, salivary glands, etc., and miscellaneous tumours, such as neurogenic tumours, it is impossible to generate a uniform staging system that would be relevant for all tumours arising in the head and neck region. In current practice, information obtained from the clinical examination and radiologic imaging is used to assign a clinical stage (cTNM). This is then used to stratify patients for a selection of therapy and to report outcomes

For many decades, the AJCC-UICC TNM staging system has been used worldwide for staging head and neck cancer [12, 13]. This system has been periodically revised for improvement. According to this, the cervical lymph nodes are divided into seven levels or groups, which are based on the extent and level of cervical nodal involvement by metastatic tumour. Although this classification of cervical lymph nodes is commonly used, especially by surgeons and oncologists, some important lymph nodes, such as parotid and retropharyngeal nodes, are not

**4. Clinical staging of cervical lymph nodes in head and neck cancer**

of the treatment.

included in this classification.

156 Contemporary Issues in Head and Neck Cancer Management

**Table 2.** N staging for tumours of the nasopharynx - AJCC/UICC 2002 [12, 13].


\*Regional nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.

**Table 3.** N staging for tumours of the thyroid - AJCC/UICC 2002 [12, 13].

The **TNM** staging system is widely used to assess prognosis, determine treatment and compare results from different protocols. However, it has a few pitfalls. The palpable lymph node in the neck does not always mean that it is metastatic and a non-palpable does not always mean that it is non-metastatic. They may contain micrometastases and may be discovered on a histological examination, which were thought to be normal on palpation and imaging.

One or more non-painful nodes in asymptomatic patients or patients with an already diag‐ nosed malignancy in the T1-T2 stage in satellite or non-satellite locations are considered as risky nodes. Furthermore, in patients with an already diagnosed malignancy in the T3-T4 stage, three or more > 2 cm nodes in a satellite location are called end–stage nodes [14].

TNM staging systems are based on clinical findings. However, imaging should be a necessary part of this staging or it should always be used to support the staging. If the imaging comple‐ ments the clinical examination, the following staging conversions can occur: N0 will become N1 neck, N1 will become N2 neck, N1 will become N3c neck or N0 will become N3c neck [15].

## **5. Diagnosis and investigations for metastatic lymph nodes in head and neck cancer**

Imaging plays an important role in the evaluation of disease in the cervical lymph nodes and should be a part of any thorough workup of patients with head and neck cancer. The contin‐ uous advances in techniques have led to the increased sensitivity of the imaging modalities in the detection of lymph nodes. Various imaging techniques are used for the detection of enlarged nodes, including ultrasound, Colour Doppler ultrasound, computed tomography, magnetic resonance imaging positron emission tomography (PET), lymphoscintigraphy and USG-guided fine-needle cytology, etc. Each imaging modality has advantages and disadvan‐ tages [16].

## **5.1. Ultrasound and colour doppler ultrasound examination of neck in head and neck cancer**

Ultrasound (US) is a non-invasive, easily accessible and comparatively cheaper imaging modality, which is used for the evaluation of cervical lymphadenopathy. The sonologist is often the first person to identify the presence of an abnormal node. Several studies have shown that sonography has a markedly higher sensitivity than palpation for the detec‐ tion of enlarged lymph nodes in patients with suspected regional lymph node metasta‐ ses, particularly in the presence of severe postoperative scarring. The use of sonography also allows the assessment of the infiltration of blood vessels and organs, such as the thyroid gland, by adjacent nodal metastases and an accurate follow-up of patients receiving chemotherapy or radiation therapy [17].

The AJCC classification for cervical lymph nodes in head and neck cancer is not specific for the ultrasound examination. This is because some lymph nodes in the classification, such as prelaryngeal, paratracheal and upper mediastinal nodes, may not be accessible via ultrasound. In 1986, Hajek et al. established another classification of cervical lymph nodes in order to simplify ultrasound examinations of the neck. According to this, the cervical lymph nodes are classified into eight regions based on their location in the neck, as shown in Figure 3 [18].

**Figure 3.** Classification of cervical lymph nodes for US examination [18].

The **TNM** staging system is widely used to assess prognosis, determine treatment and compare results from different protocols. However, it has a few pitfalls. The palpable lymph node in the neck does not always mean that it is metastatic and a non-palpable does not always mean that it is non-metastatic. They may contain micrometastases and may be discovered on a histological examination, which were thought to be normal on palpation and imaging.

One or more non-painful nodes in asymptomatic patients or patients with an already diag‐ nosed malignancy in the T1-T2 stage in satellite or non-satellite locations are considered as risky nodes. Furthermore, in patients with an already diagnosed malignancy in the T3-T4 stage,

TNM staging systems are based on clinical findings. However, imaging should be a necessary part of this staging or it should always be used to support the staging. If the imaging comple‐ ments the clinical examination, the following staging conversions can occur: N0 will become N1 neck, N1 will become N2 neck, N1 will become N3c neck or N0 will become N3c neck [15].

**5. Diagnosis and investigations for metastatic lymph nodes in head and**

Imaging plays an important role in the evaluation of disease in the cervical lymph nodes and should be a part of any thorough workup of patients with head and neck cancer. The contin‐ uous advances in techniques have led to the increased sensitivity of the imaging modalities in the detection of lymph nodes. Various imaging techniques are used for the detection of enlarged nodes, including ultrasound, Colour Doppler ultrasound, computed tomography, magnetic resonance imaging positron emission tomography (PET), lymphoscintigraphy and USG-guided fine-needle cytology, etc. Each imaging modality has advantages and disadvan‐

**5.1. Ultrasound and colour doppler ultrasound examination of neck in head and neck cancer** Ultrasound (US) is a non-invasive, easily accessible and comparatively cheaper imaging modality, which is used for the evaluation of cervical lymphadenopathy. The sonologist is often the first person to identify the presence of an abnormal node. Several studies have shown that sonography has a markedly higher sensitivity than palpation for the detec‐ tion of enlarged lymph nodes in patients with suspected regional lymph node metasta‐ ses, particularly in the presence of severe postoperative scarring. The use of sonography also allows the assessment of the infiltration of blood vessels and organs, such as the thyroid gland, by adjacent nodal metastases and an accurate follow-up of patients receiving

The AJCC classification for cervical lymph nodes in head and neck cancer is not specific for the ultrasound examination. This is because some lymph nodes in the classification, such as prelaryngeal, paratracheal and upper mediastinal nodes, may not be accessible via ultrasound. In 1986, Hajek et al. established another classification of cervical lymph nodes in order to

three or more > 2 cm nodes in a satellite location are called end–stage nodes [14].

158 Contemporary Issues in Head and Neck Cancer Management

**neck cancer**

tages [16].

chemotherapy or radiation therapy [17].

In an ultrasound examination of neck lymphadenopathy, the distribution, size, shape, nodal border, echogenic hilus, intranodal necrosis and calcification are the evaluated features. In an ultrasound examination of neck lymphadenopathy, the distribution, size, shape, nodal border, echogenic hilus, intranodal necrosis and calcification are the evaluated features.

The size of normal cervical lymph nodes differs with the location in the various regions of the neck and thus, it cannot be used as an absolute criterion for the diagnosis of metastatic lymphadenopathy. The inflammatory nodes can be as large as malignant nodes, whilst a malignancy can be found in small nodes. It has been reported that the lymph nodes in the upper neck tend to be larger than those in the lower neck. The shape of lymph nodes is usually assessed by the short axis diameter: long axis diameter (S:L The size of normal cervical lymph nodes differs with the location in the various regions of the neck and thus, it cannot be used as an absolute criterion for the diagnosis of metastatic lymphadenopathy. The inflammatory nodes can be as large as malignant nodes, whilst a malignancy can be found in small nodes. It has been reported that the lymph nodes in the upper neck tend to be larger than those in the lower neck.

ratio). A lymph node with an S:L ratio less than 0.5 is oval in shape, whereas an S:L ratio greater than or equal to 0.5 indicates round node. An oval node indicates normality, whereas malignant nodes tend to be round in shape as shown in Figure 4 and 5. Figure 4 - Sonogram showing oval reactive lymph nodes. The shape of lymph nodes is usually assessed by the short axis diameter: long axis diameter (S:L ratio). A lymph node with an S:L ratio less than 0.5 is oval in shape, whereas an S:L ratio greater than or equal to 0.5 indicates round node. An oval node indicates normality, whereas malignant nodes tend to be round in shape as shown in Figure 4 and 5.

There is a difference in the border of malignant and reactive or normal nodes. The metastatic and lymphomatous nodes have sharp borders, whereas unsharp borders are seen in reactive or normal nodes. The presence of a sharp border in malignant nodes is believed to be due to the infiltrating tumour cells replacing the normal intranodal lymphoid tissue. This causes an increase in the acoustic impedance difference between the lymph nodes and surrounding tissues.

As far as the presence of hilum is concerned, the absence of it in a lymph node is a sign of metastasis or malignant lymphadenopathy, as shown in Figure 6 and 7.

9

than those in the lower neck.

Figure 4 - Sonogram showing oval reactive lymph nodes.

border, echogenic hilus, intranodal necrosis and calcification are the evaluated features.

**Submental** 

**Parotid**

**Submandibular** 

**Upper cervical**

**Middle cervical**

**Lower cervical**

**Supraclavicular** 

accessory chain)

In an ultrasound examination of neck lymphadenopathy, the distribution, size, shape, nodal

The size of normal cervical lymph nodes differs with the location in the various regions of the

The shape of lymph nodes is usually assessed by the short axis diameter: long axis diameter (S:L

neck and thus, it cannot be used as an absolute criterion for the diagnosis of metastatic lymphadenopathy. The inflammatory nodes can be as large as malignant nodes, whilst a malignancy can be found in small nodes. It has been reported that the lymph nodes in the upper neck tend to be larger

ratio). A lymph node with an S:L ratio less than 0.5 is oval in shape, whereas an S:L ratio greater than or equal to 0.5 indicates round node. An oval node indicates normality, whereas malignant nodes tend to be

**Posterior triangle** (also known as

**Figure 4.** Sonogram showing oval reactive lymph nodes. Figure 5 - Sonogram showing round metastatic or malignant lymph node.

9

10

**Figure 5.** Sonogram showing round metastatic or malignant lymph node.

In an ultrasound examination of lymph nodes, sonologists examine intranodal necrosis and calcification. However, these examinations contribute little to the diagnosis of malignant characteristics of lymph nodes. The reason for this is that intranodal necrosis may be present in other conditions like tuberculous lymphadenopathy. Similarly, intranodal calcification also does not aid the diagnosis of malignant lymphadenopathy. This is because there are other well known causes of lymph node calcification including BCG vaccination, sarcoidosis, cat scratch disease, tuberculosis, lymphoma and fungal infections, which have been previously treated with radiation therapy. There is a difference in the border of malignant and reactive or normal nodes. The metastatic and lymphomatous nodes have sharp borders, whereas unsharp borders are seen in reactive or normal nodes. The presence of a sharp border in malignant nodes is believed to be due to the infiltrating tumour cells replacing the normal intranodal lymphoid tissue. This causes an increase in the acoustic impedance difference between the lymph nodes and surrounding tissues. As far as the presence of hilum is concerned, the absence of it in a lymph node is a sign of metastasis or malignant lymphadenopathy, as shown in Figure 6 and 7.

Figure 6 - Sonogram depicting intact hilum suggestive of benign lymph node.

Figure 7 - Sonogram showing metastatic lymph node depicting absence of hilum.

10

11

There is a difference in the border of malignant and reactive or normal nodes. The metastatic and

As far as the presence of hilum is concerned, the absence of it in a lymph node is a sign of

lymphomatous nodes have sharp borders, whereas unsharp borders are seen in reactive or normal nodes. The presence of a sharp border in malignant nodes is believed to be due to the infiltrating tumour cells replacing the normal intranodal lymphoid tissue. This causes an increase in the acoustic impedance

**Figure 6.** Sonogram depicting intact hilum suggestive of benign lymph node.

Figure 6 - Sonogram depicting intact hilum suggestive of benign lymph node.

Figure 5 - Sonogram showing round metastatic or malignant lymph node.

9

difference between the lymph nodes and surrounding tissues.

metastasis or malignant lymphadenopathy, as shown in Figure 6 and 7.

10

pathology present within the lymph node.

systolic/diastolic flow variation [19, 20].

angiogenesis factor [19].

**Figure 7.** Sonogram showing metastatic lymph node depicting absence of hilum.

resistance have been used as key features to differentiate benign from malignant nodes.

In an ultrasound examination of lymph nodes, sonologists examine intranodal necrosis and calcification. However, these examinations contribute little to the diagnosis of malignant characteristics of lymph nodes. The reason for this is that intranodal necrosis may be present in other conditions like tuberculous lymphadenopathy. Similarly, intranodal calcification also does not aid the diagnosis of malignant lymphadenopathy. This is because there are other well known causes of lymph node calcification including BCG vaccination, sarcoidosis, cat scratch disease, tuberculosis, lymphoma and fungal infections, which have been previously treated

Figure 6 - Sonogram depicting intact hilum suggestive of benign lymph node.

Figure 7 - Sonogram showing metastatic lymph node depicting absence of hilum.

difference between the lymph nodes and surrounding tissues.

**Figure 5.** Sonogram showing round metastatic or malignant lymph node.

metastasis or malignant lymphadenopathy, as shown in Figure 6 and 7.

There is a difference in the border of malignant and reactive or normal nodes. The metastatic and

As far as the presence of hilum is concerned, the absence of it in a lymph node is a sign of

lymphomatous nodes have sharp borders, whereas unsharp borders are seen in reactive or normal nodes. The presence of a sharp border in malignant nodes is believed to be due to the infiltrating tumour cells replacing the normal intranodal lymphoid tissue. This causes an increase in the acoustic impedance

**Submental** 

**Parotid**

**Submandibular** 

**Upper cervical**

**Middle cervical**

**Lower cervical**

**Supraclavicular** 

accessory chain)

In an ultrasound examination of neck lymphadenopathy, the distribution, size, shape, nodal

The size of normal cervical lymph nodes differs with the location in the various regions of the

The shape of lymph nodes is usually assessed by the short axis diameter: long axis diameter (S:L

neck and thus, it cannot be used as an absolute criterion for the diagnosis of metastatic lymphadenopathy. The inflammatory nodes can be as large as malignant nodes, whilst a malignancy can be found in small nodes. It has been reported that the lymph nodes in the upper neck tend to be larger

ratio). A lymph node with an S:L ratio less than 0.5 is oval in shape, whereas an S:L ratio greater than or equal to 0.5 indicates round node. An oval node indicates normality, whereas malignant nodes tend to be

border, echogenic hilus, intranodal necrosis and calcification are the evaluated features.

Figure 4 - Sonogram showing oval reactive lymph nodes.

Figure 5 - Sonogram showing round metastatic or malignant lymph node.

**Posterior triangle** (also known as

with radiation therapy.

than those in the lower neck.

round in shape as shown in Figure 4 and 5.

160 Contemporary Issues in Head and Neck Cancer Management

**Figure 4.** Sonogram showing oval reactive lymph nodes.

One of the advancements in ultrasonography, Colour Doppler ultrasound, can be used to define the morphologic and vascular characteristics of lymphadenopathies. Colour Doppler sonography provides information about the presence of intranodal vascularity and estimates the intravascular resistance. In Colour Doppler sonography, the pattern of vascular flow and presence of high intranodal vascular resistance have been used as key features to differentiate benign from malignant nodes. In an ultrasound examination of lymph nodes, sonologists examine intranodal necrosis and calcification. However, these examinations contribute little to the diagnosis of malignant characteristics of lymph nodes. The reason for this is that intranodal necrosis may be present in other conditions like tuberculous lymphadenopathy. Similarly, intranodal calcification also does not aid the diagnosis of malignant lymphadenopathy. This is because there are other well known causes of lymph node calcification including BCG vaccination, sarcoidosis, cat scratch disease, tuberculosis, lymphoma and

The status of the vasculature of the lymph nodes provides additional information in the sonographic examination of cervical lymph nodes. The vascularity of the lymph node gives direction for diagnosing the cause of lymphadenopathy. This is because vascularity is directly related to the actual pathology present within the lymph node. fungal infections, which have been previously treated with radiation therapy. One of the advancements in ultrasonography, Colour Doppler ultrasound, can be used to define the morphologic and vascular characteristics of lymphadenopathies. Colour Doppler sonography provides information about the presence of intranodal vascularity and estimates the intravascular resistance. In

The status of the vasculature of the lymph nodes provides additional information in the

The characteristic event in tumour formation is angiogenesis. The morphologic and

Tumour neovascularity has a particular set of characteristics. The vessels in the tumour are

Colour Doppler sonography, the pattern of vascular flow and presence of high intranodal vascular

sonographic examination of cervical lymph nodes. The vascularity of the lymph node gives direction for diagnosing the cause of lymphadenopathy. This is because vascularity is directly related to the actual

haemodynamic changes that occur in tumour vessels help to differentiate between malignant and benign lymph nodes in a Colour Doppler evaluation. In malignant or metastatic nodes, vascular structures are usually deformed due to the destruction caused by tumour infiltration and neovascularization induced by

abnormal and show an irregular course without the progressive diminution in calibre. Furthermore, they may demonstrate arteriovenous shunting and bizarre thin walled vessels lined by tumour cells may end in amorphous spaces. The characteristic feature of tumours stimulating the growth of new vessels assists in the evaluation of metastatic nodes via Doppler sonography. The tumour vessels have a relative paucity of smooth muscle in their walls, compared to their calibre. This lack of muscular elements is reflected in the low impedance to flow, leading to a high diastolic flow and, in some tumours, the absence of The characteristic event in tumour formation is angiogenesis. The morphologic and haemo‐ dynamic changes that occur in tumour vessels help to differentiate between malignant and benign lymph nodes in a Colour Doppler evaluation. In malignant or metastatic nodes, vascular structures are usually deformed due to the destruction caused by tumour infiltration and neovascularization induced by angiogenesis factor [19].

Tumour neovascularity has a particular set of characteristics. The vessels in the tumour are abnormal and show an irregular course without the progressive diminution in calibre. Furthermore, they may demonstrate arteriovenous shunting and bizarre thin walled vessels lined by tumour cells may end in amorphous spaces. The characteristic feature of tumours stimulating the growth of new vessels assists in the evaluation of metastatic nodes via Doppler sonography. The tumour vessels have a relative paucity of smooth muscle in their walls, compared to their calibre. This lack of muscular elements is reflected in the low impedance to flow, leading to a high diastolic flow and, in some tumours, the absence of systolic/diastolic flow variation [19, 20]. Both the angioarchitecture and haemodynamic differ among various cervical nodal diseases.

Both the angioarchitecture and haemodynamic differ among various cervical nodal diseases. Blood vessel morphology in metastatic nodes is usually deranged as internal nodal architec‐ ture, which is destroyed by neoplastic infiltration. Small arteries in metastatic nodes may be destroyed by tumour tissue, whereas inflammation causes the dilatation of intranodal vessels due to local humoral agents. All of these intranodal vascular alterations aid in the differentia‐ tion of malignant lymph nodes by CDUS. This is because reactive or benign nodes tend to have prominent hilar/central vascularity and metastatic or malignant nodes have peripheral or no vascularity [21]. See Figure 8 and 9. Blood vessel morphology in metastatic nodes is usually deranged as internal nodal architecture, which is destroyed by neoplastic infiltration. Small arteries in metastatic nodes may be destroyed by tumour tissue, whereas inflammation causes the dilatation of intranodal vessels due to local humoral agents. All of these intranodal vascular alterations aid in the differentiation of malignant lymph nodes by CDUS. This is because reactive or benign nodes tend to have prominent hilar/central vascularity and metastatic or malignant nodes have peripheral or no vascularity [21]. See Figure 8 and 9.

Figure 8 - Color Doppler sonogram showing a lymph node with central vascular flow.

12

**Figure 8.** Color Doppler sonogram showing a lymph node with central vascular flow.

Figure 9 - Color Doppler sonogram showing a lymph node with absence of vascular flow.

12

13

Both the angioarchitecture and haemodynamic differ among various cervical nodal diseases.

Blood vessel morphology in metastatic nodes is usually deranged as internal nodal architecture, which is destroyed by neoplastic infiltration. Small arteries in metastatic nodes may be destroyed by tumour tissue, whereas inflammation causes the dilatation of intranodal vessels due to local humoral agents. All of these intranodal vascular alterations aid in the differentiation of malignant lymph nodes by CDUS. This is because reactive or benign nodes tend to have prominent hilar/central vascularity and metastatic or

Figure 8 - Color Doppler sonogram showing a lymph node with central vascular flow.

malignant nodes have peripheral or no vascularity [21]. See Figure 8 and 9.

**Figure 9.** Color Doppler sonogram showing a lymph node with absence of vascular flow. In advanced stages of the disease, tumour cells grow and replace a large portion of the lymph node. When the lymph node is totally replaced by the tumour cells, the tumour cells compress vessels in

lymph node with peripheral Colour Doppler flow and a high resistivity index and pulsatility index.

The characteristic event in tumour formation is angiogenesis. The morphologic and haemo‐ dynamic changes that occur in tumour vessels help to differentiate between malignant and benign lymph nodes in a Colour Doppler evaluation. In malignant or metastatic nodes, vascular structures are usually deformed due to the destruction caused by tumour infiltration

Tumour neovascularity has a particular set of characteristics. The vessels in the tumour are abnormal and show an irregular course without the progressive diminution in calibre. Furthermore, they may demonstrate arteriovenous shunting and bizarre thin walled vessels lined by tumour cells may end in amorphous spaces. The characteristic feature of tumours stimulating the growth of new vessels assists in the evaluation of metastatic nodes via Doppler sonography. The tumour vessels have a relative paucity of smooth muscle in their walls, compared to their calibre. This lack of muscular elements is reflected in the low impedance to flow, leading to a high diastolic flow and, in some tumours, the absence of systolic/diastolic

Both the angioarchitecture and haemodynamic differ among various cervical nodal diseases. Blood vessel morphology in metastatic nodes is usually deranged as internal nodal architec‐ ture, which is destroyed by neoplastic infiltration. Small arteries in metastatic nodes may be destroyed by tumour tissue, whereas inflammation causes the dilatation of intranodal vessels due to local humoral agents. All of these intranodal vascular alterations aid in the differentia‐ tion of malignant lymph nodes by CDUS. This is because reactive or benign nodes tend to have prominent hilar/central vascularity and metastatic or malignant nodes have peripheral or no

Blood vessel morphology in metastatic nodes is usually deranged as internal nodal architecture, which is destroyed by neoplastic infiltration. Small arteries in metastatic nodes may be destroyed by tumour tissue, whereas inflammation causes the dilatation of intranodal vessels due to local humoral agents. All of these intranodal vascular alterations aid in the differentiation of malignant lymph nodes by CDUS. This is because reactive or benign nodes tend to have prominent hilar/central vascularity and metastatic or

Figure 8 - Color Doppler sonogram showing a lymph node with central vascular flow.

Figure 9 - Color Doppler sonogram showing a lymph node with absence of vascular flow.

**Figure 8.** Color Doppler sonogram showing a lymph node with central vascular flow.

Both the angioarchitecture and haemodynamic differ among various cervical nodal diseases.

and neovascularization induced by angiogenesis factor [19].

162 Contemporary Issues in Head and Neck Cancer Management

flow variation [19, 20].

vascularity [21]. See Figure 8 and 9.

malignant nodes have peripheral or no vascularity [21]. See Figure 8 and 9.

In advanced stages of the disease, tumour cells grow and replace a large portion of the lymph node. When the lymph node is totally replaced by the tumour cells, the tumour cells compress vessels in the lymph node. This vascular compression by the tumour cells increases vascular resistance, causing an increase in resistive index. These higher resistive indices can be observed in the metastatic/malignant lymph nodes by CDUS [21], as shown in Figure 10. the lymph node. This vascular compression by the tumour cells increases vascular resistance, causing an increase in resistive index. These higher resistive indices can be observed in the metastatic/malignant lymph nodes by CDUS [21], as shown in Figure 10. Figure 10 - Colour Doppler sonogram with Doppler spectral waveform, showing a malignant cervical

Although Colour Doppler evaluation cannot replace the histopathological procedure in knowing the status of cervical lymphadenopathy, it plays a definite role as an adjunct to the clinical evaluation of **Figure 10.** Colour Doppler sonogram with Doppler spectral waveform, showing a malignant cervical lymph node with peripheral Colour Doppler flow and a high resistivity index and pulsatility index.

cervical lymphadenopathy and proves its value as an important investigation [22]. Although Colour Doppler evaluation cannot replace the histopathological procedure in knowing the status of cervical lymphadenopathy, it plays a definite role as an adjunct to the

The radiographic evaluation of the status of lymph nodes is routinely performed on the basis of

Several studies have described the radio-morphologic characteristics of lymph node metastases

On a CT and MRI, axial scans are usually performed. These only demonstrate the nodes in the

It is important to estimate the status of regional lymph nodes in cancer of any body part. In head

in computed tomography (CT) and in magnetic resonance imaging (MRI). In computed tomography, the presence of a central hypodensity in a lymph node metastasis of a squamous epithelial carcinoma is considered a sign of nodal necrosis. In magnetic resonance imaging, a central necrosis appears in the T1-weighted as a central hypointensity and in the T2-weighted image as a central hyperintensity [23].

transverse plane, where they tend to appear round or oval. Although images can be reconstructed to coronal and sagittal plane, it is time consuming and in a CT, the resolution of images is usually lower. Nodal shape does not have any value in the differentiation of reactive from malignant nodes on a CT and

and neck cancer, various imaging modalities should also be performed for the detection of local metastases. This is because imaging is more accurate than clinical examination. However, the assessment of nodal disease by imaging can be challenging for the radiologist. This is because there are multiple sites to review and differing opinions regarding the criteria for abnormal nodes. Hoang et al. [25] have mentioned a systematic four-step approach for the evaluation of metastatic cervical lymph nodes on

**2. Role of CT or MRI in Diagnosis of Local Metastases in Head and Neck Cancer** 

size, morphology, shape and margins of the nodes.

12

MRI [24].

cross-sectional neck imaging.

suggestive of a malignant lesion.

clinical evaluation of cervical lymphadenopathy and proves its value as an important inves‐ tigation [22].

## **5.2. Role of CT or MRI in diagnosis of local metastases in head and neck cancer**

The radiographic evaluation of the status of lymph nodes is routinely performed on the basis of size, morphology, shape and margins of the nodes.

Several studies have described the radio-morphologic characteristics of lymph node metasta‐ ses in computed tomography (CT) and in magnetic resonance imaging (MRI). In computed tomography, the presence of a central hypodensity in a lymph node metastasis of a squamous epithelial carcinoma is considered a sign of nodal necrosis. In magnetic resonance imaging, a central necrosis appears in the T1-weighted as a central hypointensity and in the T2-weighted image as a central hyperintensity [23].

On a CT and MRI, axial scans are usually performed. These only demonstrate the nodes in the transverse plane, where they tend to appear round or oval. Although images can be recon‐ structed to coronal and sagittal plane, it is time consuming and in a CT, the resolution of images is usually lower. Nodal shape does not have any value in the differentiation of reactive from malignant nodes on a CT and MRI [24]. Figure 11 - A CT scan of a skull with contrast reveals: homogenously enhancing lesion present in the left

buccinator space, left submandibular and left jugulodigastric region lymphadenopathy. These are

**Figure 11.** A CT scan of a skull with contrast reveals: homogenously enhancing lesion present in the left buccinator space, left submandibular and left jugulodigastric region lymphadenopathy. These are suggestive of a malignant le‐ sion.

Figure 12 ‐ MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular gland and mandible suggestive of malignant lesion. It also reveals well‐defined enhancing soft tissue

lesion suggestive of lymphadenopathy (Axial view ‐ T2‐weighted image).

14

It is important to estimate the status of regional lymph nodes in cancer of any body part. In head and neck cancer, various imaging modalities should also be performed for the detection of local metastases. This is because imaging is more accurate than clinical examination. However, the assessment of nodal disease by imaging can be challenging for the radiologist. This is because there are multiple sites to review and differing opinions regarding the criteria for abnormal nodes. Hoang et al. [25] have mentioned a systematic four-step approach for the evaluation of metastatic cervical lymph nodes on cross-sectional neck imaging.

clinical evaluation of cervical lymphadenopathy and proves its value as an important inves‐

The radiographic evaluation of the status of lymph nodes is routinely performed on the basis

Several studies have described the radio-morphologic characteristics of lymph node metasta‐ ses in computed tomography (CT) and in magnetic resonance imaging (MRI). In computed tomography, the presence of a central hypodensity in a lymph node metastasis of a squamous epithelial carcinoma is considered a sign of nodal necrosis. In magnetic resonance imaging, a central necrosis appears in the T1-weighted as a central hypointensity and in the T2-weighted

On a CT and MRI, axial scans are usually performed. These only demonstrate the nodes in the transverse plane, where they tend to appear round or oval. Although images can be recon‐ structed to coronal and sagittal plane, it is time consuming and in a CT, the resolution of images is usually lower. Nodal shape does not have any value in the differentiation of reactive from

Figure 11 - A CT scan of a skull with contrast reveals: homogenously enhancing lesion present in the left buccinator space, left submandibular and left jugulodigastric region lymphadenopathy. These are

Figure 12 ‐ MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular gland and mandible suggestive of malignant lesion. It also reveals well‐defined enhancing soft tissue

**Figure 11.** A CT scan of a skull with contrast reveals: homogenously enhancing lesion present in the left buccinator space, left submandibular and left jugulodigastric region lymphadenopathy. These are suggestive of a malignant le‐

lesion suggestive of lymphadenopathy (Axial view ‐ T2‐weighted image).

14

**5.2. Role of CT or MRI in diagnosis of local metastases in head and neck cancer**

of size, morphology, shape and margins of the nodes.

164 Contemporary Issues in Head and Neck Cancer Management

image as a central hyperintensity [23].

malignant nodes on a CT and MRI [24].

suggestive of a malignant lesion.

sion.

tigation [22].

Figure 13 ‐ MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular gland and mandible, suggestive of a malignant lesion. It also reveals a well‐defined enhancing soft tissue lesion, suggestive of lymphadenopathy (coronal view ‐ T1‐weighted image). **Figure 12.** MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular gland and man‐ dible suggestive of malignant lesion. It also reveals well-defined enhancing soft tissue lesion suggestive of lymphaden‐ opathy (Axial view - T2-weighted image).

In doubtful cases of CT or MRI criteria, ultrasound is an excellent second-line tool, which can be used for evaluating these suspicious nodes and can also guide fine-needle aspiration to obtain cytology.

In oncology, the use of 18-fluorodeoxyglucose (FDG) PET has grown rapidly. This is a metabolic imaging tool that provides information beyond the anatomical constraints of conventional imaging. It can establish whether or not enlarged lymph nodes contain a tumour or are reactive. In 2005, Hain stated that PET has found more than 40% of metastases in lymph nodes smaller than 1 cm. However, the disadvantage of PET is that false positives can be found in infected nodes [26].

Kubicek et al. stated that PET and PET/CT scans have the potential to improve treatment outcomes by providing improved lymph node staging and prognostic factors [27].

Lymphoscintigraphy has been used to evaluate lymph node function. It is less invasive for delineating drainage and can help to visualize changes in the function [28].

In doubtful cases of CT or MRI criteria, ultrasound is an excellent second-line tool, which can be used for evaluating these suspicious nodes and can also guide fine-needle aspiration to obtain cytology.

In oncology, the use of 18-fluorodeoxyglucose (FDG) PET has grown rapidly. This is a metabolic imaging tool that provides information beyond the anatomical constraints of conventional imaging. It can establish whether or not enlarged lymph nodes contain a tumour or are reactive. In 2005, Hain stated that

15

lesion, suggestive of lymphadenopathy (coronal view ‐ T1‐weighted image).

Figure 13 ‐ MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular

In doubtful cases of CT or MRI criteria, ultrasound is an excellent second-line tool, which can be used for evaluating these suspicious nodes and can also guide fine-needle aspiration to obtain cytology. **Figure 13.** MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular gland and man‐ dible, suggestive of a malignant lesion. It also reveals a well-defined enhancing soft tissue lesion, suggestive of lym‐ phadenopathy (coronal view - T1-weighted image).

Elsewhere in the body, lymphangiography and lymphoscintigraphy are useful as these investigations provide a combination of anatomic and physiological information about lymph nodes. However, these are of no use in the neck. Both of these are invasive and can be technically difficult. MR imaging performed after the administration of superparamagnetic iron oxide particles, another hybrid of anatomic and physiological assessment, has still not been fully evaluated and is not widely available. Metabolic (functional or physiological) imaging with fluorine-18-fluorodeoxyglucose positron emission tomography is new and promising. The limited anatomic detail that positron emission tomography provides will likely require correlation with CT or MR imaging to make it widely useful. In oncology, the use of 18-fluorodeoxyglucose (FDG) PET has grown rapidly. This is a metabolic imaging tool that provides information beyond the anatomical constraints of conventional imaging. It can establish whether or not enlarged lymph nodes contain a tumour or are reactive. In 2005, Hain stated that

15

Several studies suggested that new and highly sensitive investigations, in particular immu‐ nohistochemistry, molecular analysis, polymerase chain reaction (PCB) and serial sectioning of cervical lymph nodes, have increased the detection rate of micrometastases in head and neck cancers [29].

In addition to imaging techniques, the use of biomarkers studied on a protein, DNA or RNA level may be useful for the assessment of regional metastasis in head and neck squamous cell carcinoma [30].

FNAC and biopsy are considered confirmatory tests for the diagnosis of lymphadenopathy but these have a certain lacunae. For example, Ying et al. [18] stated in their review that it is difficult to collect adequate tissue volume from small lymph nodes and from post-irradiation nodes. According to them, it has been reported that 15% of specimens from US guided FNA did not provide an accurate diagnosis due to an uncertain diagnosis or inadequate sample. In the neck, FNA is usually difficult in a lymph node that is situated in the deep submandibular area.

Sato et al. [31] stated that puncturing the metastatic node with a needle could not be indicated in all situations because of the risks of micro dissemination of cancer cells, rupture of the capsule of the metastatic node and infection after FNAB.

## **6. Treatment related significance of cervical lymphadenopathy in head and neck cancer**

Localized tumours that do not metastasize have the best prognosis. Cancers that have metastasized usually indicate a later stage disease and treatment becomes more complicated, with poorer outcomes. During the surgical treatment of a tumour, the nearby lymph nodes are also removed. This is because these are frequently the first sites of the cancer metastasis.

Current treatment strategies in oral cancer rely on staging based on the imaging techniques to detect regional metastasis. However, no strategies challenge the gold standard of histopatho‐ logical examination of the neck dissection [32]. Nevertheless, various imaging madalities may direct the surgeons to convert the treatment plan to choose a more conservative neck dissection or, after frozen section control, to convert the treatment to a more radical dissection.

In conclusion, the presence of local metastases influences the treatment and prognosis of head and neck cancer. The traditional approach of treating all necks by considering the significant risk of having occult lymph node metastases may result in the unnecessary removal of regional lymph nodes, which ultimately prove to be pathologically free of cancer. Imaging plays a vital role in detecting the status of regional lymph nodes. For each and every patient of head and neck cancer, pretreatment imaging should be a protocol used to help to decide the appropriate treatment. Imaging performed before surgical treatment will aid in reducing mortality and morbidity.

## **7. Conclusion**

15

Elsewhere in the body, lymphangiography and lymphoscintigraphy are useful as these investigations provide a combination of anatomic and physiological information about lymph nodes. However, these are of no use in the neck. Both of these are invasive and can be technically difficult. MR imaging performed after the administration of superparamagnetic iron oxide particles, another hybrid of anatomic and physiological assessment, has still not been fully evaluated and is not widely available. Metabolic (functional or physiological) imaging with fluorine-18-fluorodeoxyglucose positron emission tomography is new and promising. The limited anatomic detail that positron emission tomography provides will likely

imaging tool that provides information beyond the anatomical constraints of conventional imaging. It can establish whether or not enlarged lymph nodes contain a tumour or are reactive. In 2005, Hain stated that

used for evaluating these suspicious nodes and can also guide fine-needle aspiration to obtain cytology.

**Figure 13.** MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular gland and man‐ dible, suggestive of a malignant lesion. It also reveals a well-defined enhancing soft tissue lesion, suggestive of lym‐

In doubtful cases of CT or MRI criteria, ultrasound is an excellent second-line tool, which can be

In oncology, the use of 18-fluorodeoxyglucose (FDG) PET has grown rapidly. This is a metabolic

Figure 13 ‐ MRI reveals intense enhancing soft tissue mass involving gingiva, alveolus, submandibular gland and mandible, suggestive of a malignant lesion. It also reveals a well‐defined enhancing soft tissue

lesion, suggestive of lymphadenopathy (coronal view ‐ T1‐weighted image).

166 Contemporary Issues in Head and Neck Cancer Management

Several studies suggested that new and highly sensitive investigations, in particular immu‐ nohistochemistry, molecular analysis, polymerase chain reaction (PCB) and serial sectioning of cervical lymph nodes, have increased the detection rate of micrometastases in head and neck

In addition to imaging techniques, the use of biomarkers studied on a protein, DNA or RNA level may be useful for the assessment of regional metastasis in head and neck squamous cell

FNAC and biopsy are considered confirmatory tests for the diagnosis of lymphadenopathy but these have a certain lacunae. For example, Ying et al. [18] stated in their review that it is difficult to collect adequate tissue volume from small lymph nodes and from post-irradiation

require correlation with CT or MR imaging to make it widely useful.

phadenopathy (coronal view - T1-weighted image).

cancers [29].

carcinoma [30].

In conclusion, the traditional approach in head neck cancer is to treat all necks by consider‐ ing the significant risk of having occult lymph node metastases. Unfortunately, this ap‐ proach often involves the unnecessary treatment of necks that ultimately prove to be pathologically free of cancer. So, we recommend the policy that for each and every patient of head and neck cancer, careful thorough evaluation should be performed by means of var‐ ious imaging modalities. This will help to decide most appropriate treatment as well as re‐ duce overall morbidity.

## **Author details**

Suwarna Dangore–Khasbage

Address all correspondence to: Dangore\_suwarna@redffmail.com

Oral Medicine and Radiology, SPDC, Datta Meghe Institute of Medical Sciences, Wardha, India

## **References**


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**Author details**

India

**References**

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## *Edited by Loredana G. Marcu*

While the management of head and neck cancer has evolved over the last few decades, there are still several challenges and unanswered questions that need solutions. This book is a small compilation of some topical aspects regarding head and neck cancer treatment, including the etiology of HPV-positive oropharyngeal cancers and risk factors in the young population, the challenge of surgical margin definition and the perennial problem of systemic treatment due to distant metastases. Radiobiological aspects are also covered through the Rs of radiotherapy, with a couple of chapters being dedicated to radioresistance and tumour microenvironment. Contemporary Issues in Head and Neck Cancer Management comes as an addition to the existing literature that aims to tackle this radiobiologically challenging tumour.

Photo by OlegMalyshev / iStock

Contemporary Issues in Head and Neck Cancer Management

Contemporary Issues in

Head and Neck Cancer

Management

*Edited by Loredana G. Marcu*