Second primary malignancies in patients with head and neck cancers

INTRODUCTION — Patients with head and neck squamous cell carcinoma (HNSCC) are at increased risk for the development of a second primary malignancy (SPM), which is defined as a second malignancy that presents either simultaneously or after the diagnosis of an index tumor. A synchronous SPM is diagnosed simultaneously or within six months of the index tumor, while a metachronous SPM is diagnosed greater than six months after the index tumor. SPMs need to be distinguished from local recurrences or metastasis of the primary tumor.

SPM represents the second leading cause of death in patients with HNSCC [1]. One-quarter to one-third of deaths in these patients are attributable to SPM [1-3], highlighting the importance of SPM in the successful management of HNSCC.

The classification, epidemiology, etiology, diagnosis, and management of SPMs of the upper aerodigestive tract after treatment of an initial head and neck cancer will be reviewed here. Surveillance for an SPM or locally recurrent disease and the management of head and neck cancer in patients who have already been treated once are discussed separately. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck" and "Treatment of locally recurrent squamous cell carcinoma of the head and neck".)

FIELD CANCERIZATION — The concept of field cancerization has been used to explain the occurrence of second primary malignancies (SPMs), especially in the oral cavity. This concept was introduced by Slaughter et al [4], who discovered that in oral cancers, the epithelium beyond the boundaries of the tumor possessed histologic changes. The classic view of the term "field cancerization" hypothesized that large areas of head and neck mucosa are affected by carcinogen exposure, resulting in a wide field of premalignant disease that gives rise to multiple independent primary tumors. (See "Head and neck squamous cell carcinogenesis: Molecular and genetic alterations", section on 'Field cancerization'.)

Some, but not all, studies have found that putative SPMs share a genetic pattern with the primary tumor, with both tumors originating from a common clone [5,6].

●In one study, microsatellite analysis showed that three of five patients with synchronous oral cavity cancers shared all loss of heterozygosity markers, suggesting a common clonal origin in a subset of patients [5].

●In another study, karyotype analysis and fluorescence in situ hybridization proved clonal relationship in a patient with floor-of-mouth and synchronous hypopharynx SPM [7].

●In contrast, in another study of 17 patients with SPMs within the upper aerodigestive tract, p53 genotyping showed complete discordance between the index tumor and the SPM [8].

HUMAN PAPILLOMAVIRUS ASSOCIATED MALIGNANCIES — Human papillomavirus (HPV) has emerged as a causative agent of oropharyngeal squamous cell carcinoma (OPSCC) [9]. HPV associated OPSCC often presents without traditional risk factors such as tobacco or alcohol; those affected tend to be younger, male, and with limited or no smoking history (table 1). The incidence of HPV associated OPSCC is rising in the United States [9]. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'Clinical presentation'.)

Because many of these patients lack the traditional risk factors present in the field cancerization model, it raises the question of whether patients with HPV associated OPSCC are at similar risk of developing secondary primary malignancy (SPM) as those with non-HPV associated head and neck cancers. Observational studies of patients with head and neck squamous cell carcinoma (HNSCC) suggest the following [10,11]:

●The overall incidence of developing an SPM is approximately 12 percent.

●In patients with OPSCC, the median time to development of an SPM after the index OPSCC is approximately two years. Patients with HPV associated tumors have a longer median time to SPM compared with those with non-HPV associated tumors.

●Patients with non-HPV associated HNSCC had a 15 percent increased risk of developing SPM compared with those with HPV associated HNSCC.

●When evaluated by subsite, the highest rates of SPM were identified when the index malignancy was in the larynx, followed by hypopharynx, and oral cavity. When the oropharynx was the index primary site, SPM rates were lowest, consistent with the observation that patients with HPV associated HNSCC are at lower risk for developing an SPM than those with non-HPV associated HNSCC.

●The site of the SPM differs by HPV status. Among HPV associated OPSCC, the most common site of SPM is the lungs, followed by the prostate, ovaries, and endometrium. In contrast, among non-HPV associated head and neck cancers, the most frequent sites of SPM are the lungs and head and neck.

●Survival after SPM in non-HPV associated HNSCC is worse when compared with patients with HPV associated HNSCC.

CLASSIFICATION CRITERIA FOR SECOND PRIMARY MALIGNANCY

Warren and Gates criteria for second primary malignancy — The classic criteria for defining second primary malignancy (SPM) were proposed by Warren and Gates [12]. These include the following:

●Histologic confirmation of malignancy in both the index and secondary tumors.

●The two malignancies must be anatomically separated by normal mucosa.

●The possibility of the SPM being a metastasis from the index tumor must be excluded.

Most investigators use these three criteria to define an SPM.

However, disagreement exists regarding the application of the second and third criteria. For example, when both tumors appear in the same anatomic subsite, there is no agreement on the distance that should exist between the tumors, with some investigators favoring 1.5 cm [5] and others requiring 2 cm [13]. Furthermore, when occurring in the same anatomic subsite, some investigators add that the SPM must present at least three years after the diagnosis of the index tumor [13], while others require that the SPM present at least five years after the index tumor [14]. Others suggest that molecular analysis is required to classify a tumor as an SPM [6].

Molecular criteria — A molecular classification system has been proposed for SPMs [6]. When dealing with two lesions within the same anatomic subsite, molecular profiling techniques can be employed to identify relationships between lesions, rather than relying on a distance between lesions or time elapsed between detection of tumors.

●If comparison of molecular patterns of first and second tumors is identical, the second tumor should be classified as either a local recurrence or metastasis.

●When some genetic markers are similar and other markers are different, this is classified as a "second field tumor." Second field tumors are believed to arise when within a large field of clonally related premalignant cells, two independent processes lead to two tumors within this field of premalignant cells.

●If the molecular profiles of the tumors are completely different, the second tumor is classified as a second primary tumor.

Distinguishing second primary lung malignancies from distant metastasis — The solitary lung nodule in a patient with head and neck squamous cell carcinoma (HNSCC) can present a particularly difficult diagnostic dilemma, since distinguishing between a second primary lung squamous cell carcinoma (SCC) and metastasis from the primary HNSCC has great influence on patient prognosis and treatment strategies. The lung is the most common site of distant metastasis in patients with HNSCC, and the incidence may be higher in patients with human papillomavirus (HPV) associated HNSCC. In addition, patients with HNSCC may also have an increased risk of second primary lung malignancies.

Comparison of genetic alterations is an important method to investigate clonal relationships between HNSCC and solitary lung SCC. Several investigators have employed mutation analysis to differentiate between lung metastasis and second primary lung malignancy when the lung lesion is of squamous origin. Second primary lung malignancies of nonsquamous origin do not require mutational analysis.

●In one study of 16 patients with HNSCC and a solitary lung SCC, use of microsatellite analysis clarified the relationship between the lung tumor and the primary HNSCC in 13 of 16 patients (81 percent) [15]. The patterns of allelic loss on chromosomal arms 3p and 9p were compared in the HNSCC and the solitary lung SCC. Clonal relationships were present in 10 of 16 patients (63 percent), suggesting metastatic spread. Completely discordant patterns of loss at all loci were identified in 3 of 16 cases (19 percent), suggesting independent tumor origin or a second primary lung malignancy. In 3 of 16 patients (19 percent), concordant allelic loss was present on one chromosomal arm while discordant loss was present on the other, and determining clonality in these cases was not possible.

●In another study, microsatellite markers on chromosome arms 3p, 9p, and 17p were used to investigate the clonality of multiple SCCs in the aerodigestive tract [16]. In eight patients with HNSCC and a solitary lung SCC, five (63 percent) were determined to have distant metastatic disease, while three (37 percent) had an SPM.

EPIDEMIOLOGY AND RISK FACTORS

Incidence — The risk of second primary malignancy (SPM) in patients who have had a head and neck squamous cell carcinoma (HNSCC) is significantly increased compared with the age-matched general population. This increased risk is largely restricted to cancers of the aerodigestive tract and remains relatively constant over time after the initial diagnosis. The incidence of SPM ranges from 2 to 7 percent per year [17-21], although the incidence of SPM is believed to be decreasing, which is perceived to be due to lower rates of SPM in human papillomavirus (HPV) associated oropharyngeal cancer [10,22]. The risk of developing an SPM has been shown to remain constant from the time of initial diagnosis throughout the lifetime of the patient [18]. However, emerging data show that the risk of developing an SPM rises exponentially over time, with SPM risks of 4, 10, and 25 percent at 5, 10, and 15 years, respectively [23]. These data support the long-term follow-up of patients with HNSCC, as the risk of developing an SPM extends well beyond five years of the treatment of the index tumor.

Several large, contemporary cancer registry studies provide insights into the magnitude and details of the increased risk [14,24]:

●An analysis of 13 cancer registries in Europe, Asia, Australia, and Canada provides data on over 99,000 patients and approximately 490,000 person-years of follow-up [24]. In this combined database, 10,826 second primaries were identified:

•The 20-year cumulative risk of a second cancer was 36 percent, and the standardized incidence ratio (SIR) compared with the general population was 1.86. The SIR is defined as the ratio of observed to expected second cancers [25,26].

•The most frequent second malignancy was lung cancer (20-year cumulative risk 13 percent, SIR 3.3).

•The highest relative increase in risk was for a second head and neck cancer (SIR 11.2).

•The increased risk of an SPM decreased with increasing age at the diagnosis of the first cancer. As an example, for patients with a second primary head and neck cancer, the SIR decreased progressively from 14.9 for those less than 56 years of age at the initial diagnosis to 8.4 for those 75 years of age or older. A similar progressive decrease in risk was observed for patients whose second primary was in the lung. Whether this reflected higher background rates of cancer with increasing age in the general population or the effect of other unidentified factors (tobacco, alcohol, genetics) is unclear.

●A second study analyzed the frequency of second malignancies in 75,087 patients identified between 1975 and 2006 from the Surveillance, Epidemiology, and End Results (SEER) database [14]:

•The SIR for a second primary solid tumor was 2.2. This corresponded to an excess absolute risk of 168 cancers per 10,000 patient-years at risk (PYR).

•The biggest relative increase in risk was for a second primary cancer of the head and neck (SIR 12.4), and this contributed an excess absolute risk of 60 per 10,000 PYR.

•The risk of SPM differed significantly by subsite of index HNSCC. The risk of an SPM was highest for patients with squamous cell carcinoma (SCC) of the hypopharynx, followed by oropharynx, oral cavity, and larynx (SIRs 3.5, 3, 2.8, and 1.9, respectively).

•Subsite-specific trends have changed during the human papillomavirus (HPV) era. In contrast to the other three subsites, there has been a substantial decline in the risk of SPM in patients with oropharynx primary malignancies [14,27]. Before 1990, oropharynx primary malignancies carried the second highest excess burden of SPM, whereas currently, oropharynx index cancers carry the lowest risk of SPM. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

•The incidence of lung cancer was also significantly increased (SIR 3.8). Because of the high frequency of lung cancer, this was the biggest contributor to the absolute increase in cancer incidence (excess annual risk 75 per 10,000 patient-years).

•Esophageal cancer was also markedly increased in incidence and was a significant contributor to the overall increase in cancer frequency in patients who originally presented with head and neck cancer (SIR 14.2 and excess annual risk 14.2 per 10,000 patient-years).

•There was only a minimal increase in the risk of solid tumors other than those of the head and neck, lung, and esophagus (SIR 1.1).

In one analysis of 1512 patients with primary HNSCC treated with contemporary definitive radiation therapy, the incidence of SPM was 9 percent [23]. Because inclusion criteria for this study required that the index tumor was treated nonsurgically, the majority of patients in this study had primary oropharyngeal (86 percent) or laryngeal (7 percent) cancers.

●Median time to development of SPM was 72 months, and the risk increased exponentially with time.

●Smoking was a significant risk factor for development of an SPM, and of the patients developing an SPM, 70 percent were either current smokers or had >10-pack year smoking history (risk ratio 2.14, 95% CI 1.47-3.16).

●Age, smoking status, and use of induction chemotherapy were shown to be associated with increased risk of development of SPM.

The site of the index cancer influences the most likely site of an SPM. As an example, in a series of 1257 patients with HNSCC, patients with an index malignancy arising in the larynx were more likely to develop a second primary cancer in the lung, while those arising in the oral cavity were more likely to develop a second primary in the head and neck, or esophagus [28]. This relationship has been observed in other studies as well [29,30].

Studies of the SEER cancer registry suggest that rates of SPM are lower in patients with HPV associated oropharyngeal cancers, likely due to a lack of traditional "field cancerization" associated with chronic smoking and alcohol consumption [20,22,31]. Since the SEER database does not include HPV status, these studies rely on the substantial increase in HPV associated cancer in the 1990s to demonstrate a temporal link between the era of HPV associated cancer and decreases in SPM incidence.

As an example, one study of the SEER database analyzed rates of synchronous SPM from 1979 to 2008 and showed that the risk of synchronous SPM in patients with oropharyngeal cancer declined dramatically in the 1990s, coinciding with the onset of the era of HPV associated cancer [31]. In the 1970s and 1980s, patients with oropharyngeal cancer carried the highest risk of SPM. This risk declined greatly after 1990, such that patients with oropharyngeal cancer carried the lowest risk of SPM in the 1990s and 2000s. In contrast, the rates of synchronous SPM remained unchanged during the study period for patients with cancers of the oral cavity, larynx, and hypopharynx.

Another study of the SEER database evaluated rates of metachronous SPM during the time period of 1973 to 2008, specifically evaluating rates of SPM two years following an index HNSCC [22]. Patients with high-grade oropharyngeal cancer diagnosed from 2000 to 2008 had a greater than 50 percent reduction in SPM when compared with a similar cohort diagnosed from 1973 to 1989 [22]. Among patients with high-grade oropharyngeal cancer, the incidence rates of SPM declined from 65.5 to 54.6 to 30.5 per 10,000 person-years across the time periods of 1973 to 1989 versus 1990 to 1999 versus 2000 to 2008, respectively. This dramatic decline in metachronous SPM was temporally associated with the onset of the era of HPV associated cancer.

Nasopharyngeal cancer is more frequent in Asian populations and is associated with Epstein-Barr virus (EBV). The increase in second malignancies in that population is limited to the head and neck, and there is no significant increase in lung or esophageal cancer [29]. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

Risk factors — A number of factors influence the likelihood of developing one or more additional cancers, either in the head and neck or elsewhere:

●Tobacco and alcohol use – Exposure to tobacco and alcohol is a well-known risk factor for the development of head and neck cancer and is the primary factor associated with the increased frequency of SPMs. These agents are thought to contribute to changes throughout the epithelium, and their continued use is associated with an increased risk of second malignancies. Smoking cessation appears to diminish the risk of an SPM after a diagnosis of head and neck cancer, and smoking cessation counseling is critically important. Smoking status is also associated with survival after development of an SPM [23]. (See "Epidemiology and risk factors for head and neck cancer", section on 'Risk factors' and "Overview of smoking cessation management in adults".)

●Age – Multiple large studies have observed that the risk of an SPM is increased in patients with a head and neck cancer diagnosed at a relatively early age, and that this increased risk decreases with increasing age [24,32]. Whether this reflects higher background rates of cancer with increasing age in the general population or the effect of other unidentified factors (tobacco, alcohol, genetics) is unclear. (See 'Incidence' above.)

●Prior radiation therapy – The role of prior radiation therapy is complex. Previous treatment for head and neck cancer using external beam radiation therapy is associated with a decreased incidence of second primary cancers within the treatment fields. This observation has been attributed to treatment of premalignant epithelium and occult second primary tumors. In a SEER database study of 27,985 patients, the incidence of a second primary head and neck cancer was significantly decreased in those treated with radiation therapy compared with those whose primary cancer was managed with surgery (7.7 versus 10.5 percent at 15 years) [33].

However, exposure to radiation therapy may be associated with various cancers, such as thyroid cancer or sarcoma [34].

●Other risk factors – Other risk factors associated with an increased risk of SPMs may include poor oral hygiene, immunologic factors, and genetic factors. (See "Epidemiology and risk factors for head and neck cancer".)

DIAGNOSIS — The initial evaluation of a patient with head and neck squamous cell carcinoma (HNSCC) should include direct laryngoscopy, nasopharyngoscopy, and esophagoscopy (panendoscopy) to exclude a synchronous second primary malignancy (SPM) of the upper aerodigestive tract [35].

Some authors question the cost-effectiveness of panendoscopy, given the low incidence of synchronous SPMs [36], while others have found panendoscopy to be useful, particularly in smokers, with a synchronous SPM observed in 12 percent of smoking patients [37]. Another study reported synchronous aerodigestive tract SPM in 3.9 percent of patients detected by panendoscopy during the initial evaluation of head and neck malignancy, and it advocated the importance of panendoscopy in the detection of an asymptomatic, "silent" SPM, when the likelihood of curative treatment is highest [38].

Despite the low incidence, the presence of a synchronous SPM significantly impacts the treatment plan of the individual patient, and for this reason, it is the practice of the authors to perform a thorough endoscopic evaluation under general anesthesia prior to surgical treatment of HNSCC. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Initial evaluation'.)

Positron emission tomography (PET) and computed tomography (CT) may complement or replace panendoscopy in detecting synchronous primary cancers. One large series investigating the utility of PET/CT in detecting SPM tumors published a synchronous SPM rate of 4 percent [17]. Using PET/CT during the primary staging workup, the sensitivity for detecting second primary cancers was 97.5 percent, with a negative predictive value of 99.7 percent. However, the specificity was 92.6 percent, and the positive predictive value was only 62.9 percent. These data suggest that PET/CT is a sensitive technique to detect SPMs, although some false-positive tests will occur.

At the authors' institution, panendoscopy is routinely performed for tumor-mapping purposes as well as to evaluate for an SPM in patients undergoing surgical treatment of HNSCC. For patients being managed with primary radiation therapy or chemoradiotherapy, a thorough physical examination combined with PET/CT is usually adequate, and panendoscopy is not necessary unless the patient requires tissue biopsy under general anesthesia.

Regular follow-up after treatment of an initial head and neck cancer is mandatory to identify recurrent disease and/or a potential SPM and to look for evidence of recurrent disease from the index cancer. As an example, in one study of 130 patients with SPM, nearly 50 percent were asymptomatic and the SPM was detected on routine examination and/or investigations [23]. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend the following follow-up schedule [39]:

●Year 1 – Every one to three months

●Year 2 – Every two to six months

●Years 3 to 5 – Every four to eight months

●After year 5 – Every 12 months

Although the risk of locoregional recurrence from the original tumor decreases over time, continued surveillance is needed because the increased risk of a second primary tumor can be very extended. (See 'Incidence' above and "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

MANAGEMENT — Management of second primary malignancies (SPMs) varies by tumor subsite and stage. In general, the SPM is treated in a similar fashion as a primary index tumor at the subsite of origin. A comprehensive discussion of treatment of each SPM site is beyond the scope of this chapter; however, several treatment principles are discussed below.

Second primary malignancies of the upper aerodigestive tract — The issues and difficulties associated with the treatment of a second primary head and neck malignancy are similar to those for a patient with recurrent disease (see "Treatment of locally recurrent squamous cell carcinoma of the head and neck" and "Reirradiation for locally recurrent head and neck cancer" and "Treatment of metastatic and recurrent head and neck cancer"):

●Treatment of SPMs of the upper aerodigestive tract is site specific. In general, the SPM should be treated as a separate entity, in the same manner as a primary index tumor at the anatomic subsite.

●In many cases, particularly in metachronous SPMs, patients have already received a full complement of treatment, including primary or adjuvant radiation therapy and/or chemoradiotherapy. In these cases, surgical treatment of the SPM is often indicated when feasible.

●Reirradiation is an option in carefully selected cases when salvage surgery is not possible. Proper patient selection for reirradiation is critical, and only patients with minimal comorbidity and toxicity of previous radiation therapy should be considered [40,41]. Patients at high risk for local recurrence after salvage surgery may benefit from the increased locoregional control from adjuvant reirradiation, although there is no survival advantage compared with salvage surgery alone [40].

When reirradiation is used, standard doses are required for a meaningful opportunity for local control. Factors that need to be considered include the previously treated volume and dose fractionation schedule, the critical tissues and organs at risk, and the time elapsed since the first treatment course. Local control is best with small, well-differentiated second primary tumors as opposed to recurrent disease. Reirradiation should only be considered if there are no other practical alternatives to treatment since there is an increased risk of serious complications. To minimize the risk of posttreatment complications, intensity-modulated radiation therapy should be used [42,43]. Reirradiation is associated with a significant decline in quality of life in patients with SPM due to treatment toxicity in this patient population [44]. (See "Management of late complications of head and neck cancer and its treatment".)

Treatment of second primary malignancies of the lung — Differentiating a second primary lung malignancy from distant metastasis of the head and neck squamous cell carcinoma (HNSCC) is critical. (See 'Distinguishing second primary lung malignancies from distant metastasis' above.)

In most cases, if the second primary lung malignancy fits usual criteria for resectability, surgical treatment is indicated [45]. The surgical assessment of patients with second primary lung malignancies requires careful attention to resectability and medical fitness for surgical treatment. The approach to the patient with potentially resectable primary lung cancer is discussed separately. (See "Management of stage I and stage II non-small cell lung cancer".)

Chemoprevention — The only established means to reduce the risk of an SPM is cessation of smoking. (See "Overview of smoking cessation management in adults".)

Numerous agents have been studied as potential chemopreventive agents, with a goal of reducing recurrences from the index tumor and to prevent malignant conversion of premalignant lesions. Unfortunately, none of these compounds has shown significant benefit in prospective randomized studies, and none has an established role in patients who have had HNSCC. (See "Chemoprevention and screening in oral dysplasia and squamous cell head and neck cancer".)

SURVIVAL — The prognosis of an individual patient is a function of the site and stage of the second primary, as well as comorbidities and the ability to treat the tumor in a definitive manner.

One large retrospective review of 3436 patients showed the following survival data [46]:

●Five-year survival for patients with head and neck squamous cell carcinoma (HNSCC) who did not develop a second primary malignancy (SPM) was 48 percent. Five-year survival for patients with HNSCC who developed an SPM was also 48 percent. However, survival continued to decrease over time in patients who developed an SPM, and at 15 years, tumor-specific survival was 20 percent in patients who developed an SPM compared with 44 percent in patients who did not develop an SPM. These survival data are derived from the time of the diagnosis of the index tumor.

●Five-year survival from the time of the diagnosis of the SPM was 26 percent. There was a significant improvement in survival in patients whose SPM originated in the head and neck (five-year survival 31 percent) compared with in patients whose SPM presented at distant sites (five-year survival only 8 percent).

By contrast, another study showed improved survival rates [23]:

●Five-year overall survival from the diagnosis of SPM was 44 percent with a median overall survival of 98 months. Interestingly, overall survival was not impacted by smoking status.

Factors that contribute to the prognosis following the diagnosis of SPM include the following:

●Site of the second primary – Other studies have found that SPMs arising in the lung or in the esophagus have a worse prognosis than a second head and neck primary [47]. As an example, the five-year survival rate was 61 percent in patients whose SPM arose in the head and neck versus 19 and 0 percent for second tumors of the lung and esophagus, respectively [3]. Patients with lung cancer after HNSCC have a worse prognosis than the general population of patients with lung cancer [48]. This seemed to hold up even for histologically different subtypes of cancers (eg, HNSCC versus adenocarcinoma second primary), thus excluding metastasis as an explanation. Although there are no data in this specific patient population, other high-risk populations benefit from regularly scheduled low-dose screening lung computed tomography (CT), and this should be considered for HNSCC survivors. (See "Screening for lung cancer", section on 'Low-dose chest CT'.)

●Interval between the index cancer and the second primary – Patients with a metachronous second primary have a better prognosis than those who present with synchronous lesions [32,49,50].

SUMMARY AND RECOMMENDATIONS

●Incidence of second primary malignancies after head and neck cancer – The incidence of second primary malignancies (SPMs) in patients who have had an index head and neck squamous cell carcinoma (HNSCC) is significantly increased compared with the general population. The risk of an SPM remains elevated for at least 10 years and is typically restricted to tumors arising in the head and neck, lung, and esophagus. (See 'Incidence' above.)

●Risk factors – Exposure to tobacco and alcohol is the primary factor associated with the development of SPMs. Patients with a human papillomavirus (HPV) associated HNSCC are at lower risk for developing an SPM than those with non-HPV associated HNSCC. (See 'Risk factors' above and 'Human papillomavirus associated malignancies' above.)

●SPM versus recurrent or metastatic disease – Differentiating between an SPM, locoregional recurrence, and distant metastasis is not always possible on clinical, radiologic, and pathologic grounds. Newer molecular techniques have emerged that may permit the ability to determine the clonal relationship between two malignancies. Determining whether a lesion represents an SPM or distant metastasis is critical to treatment planning. (See 'Classification criteria for second primary malignancy' above.)

●Initial evaluation – The initial evaluation of a patient with HNSCC should include a detailed history and examination to exclude a synchronous SPM. Panendoscopy and/or positron emission tomography (PET)/computed tomography (CT) may be performed during the initial evaluation to rule out an SPM. Meticulous follow-up is required for early detection of recurrent disease and SPMs. (See 'Diagnosis' above and "Overview of the diagnosis and staging of head and neck cancer" and "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

●Management – Patients presenting with an SPM in the head and neck region present a therapeutic challenge due to the previous treatment received, especially when prior treatment included radiation therapy. In general, the SPM is treated in a similar fashion as a primary index tumor at the subsite of origin. If the SPM arises in previous radiation treatment fields, surgical treatment of the SPM is often preferred. Reirradiation can be hazardous, but it may be offered in selected cases when the risk-benefit ratio is reasonable and surgery is not an option. (See 'Management' above.)

●Prognosis – Survival in patients with SPM depends on the location of the SPM. Patients with SPM arising in the head and neck have significantly improved survival when compared with patients with SPM arising in the lung and esophagus. (See 'Survival' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sandeep Samant, MD, who contributed to an earlier version of this topic review.