Multiple primary lung cancers

INTRODUCTION — Patients with lung cancer may present with two primaries at the same time (synchronous multiple primary lung cancer) or may develop a second, metachronous primary lung cancer after treatment of the initial lesion. This is becoming a more common clinical issue and remains a challenge due to how these tumors are classified [1].

Multiple primary lung cancers (MPLC) pose a variety of clinically important diagnostic and therapeutic problems, which may differ from those in patients presenting with a single primary tumor. These issues are reviewed here for both synchronous and metachronous MPLC.

DIAGNOSTIC CRITERIA

Synchronous MPLC — Patients presenting with more than one pulmonary nodule at the same time must fulfill strict criteria to be classified as having synchronous MPLC [2,3].

●Both lesions must be malignant and must arise independently in the lung. The second lesion cannot be assumed to represent a second primary lung cancer. A benign nodule, infectious process, or metastasis from an extrapulmonary site must be excluded.

●The second malignant lesion must not represent a metastasis from the first lung lesion. Accepted criteria for this distinction include [4]:

•Different histology or origin from a separate focus of carcinoma in situ.

•Same histology, but anatomically distinct, without involvement of the mediastinum (N2, N3 negative), and without systemic metastases.

•Same histology, but clearly different based upon a comprehensive histologic assessment:

-Determination of the predominant subtype

-Relative percentage of each histologic subtype estimated in 10 percent increments

-Cytological features to include: grade, necrosis, inflammation

•Different pattern of biomarkers utilizing gene sequencing technologies.

Metachronous MPLC — Patients with a history of a previously treated lung cancer are at increased risk for the development of a second lung cancer. The diagnostic issues in these patients and their subsequent management pose different issues than for synchronous MPLC.

●The differential diagnosis includes a benign nodule, infectious process, or a metastasis from extrapulmonary primary.

●The tumors are considered metachronous if the histology is different or if they are the same histology and there is a four year or greater interval between the cancers with no evidence of systemic metastases [5]. With a shorter interval between two primary tumors, the prognosis might be less favorable but the treatment options would generally be similar in the absence of other systemic metastatic disease.

TNM staging system implications — The definitions in the eighth edition of the American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) staging system have important implications for classifying a patient as having MPLC (table 1). (See "Tumor, node, metastasis (TNM) staging system for lung cancer".)

●Histologically identical lesions within the same lobe are considered to be "separate tumor nodules" and are classified as being a single T3 tumor, and this is not considered a MPLC [6].

●A secondary lesion with identical histology located in a different lobe of the ipsilateral lung is considered a T4 lesion. Thus, some cases that were previously considered as stage IV disease or MPLC in the sixth edition of the staging system are classified as T4 tumors.

Where clinical guidance is provided in this topic, the eighth edition staging system is used; however, it is recognized that the studies cited may have used previous editions of the staging system, which is a limitation of existing data.

Histology — There have been substantial changes in the prevalence of various histologies of lung cancer over the last several decades in the United States, with an increasing incidence and proportion of adenocarcinoma and a decreasing frequency of squamous cell carcinoma [7]. In an analysis of cooperative group trials in patients with non-small cell lung cancer (NSCLC), the majority of patients had adenocarcinoma (58 percent), followed by squamous (20 percent) and large cell carcinoma (8 percent) [8]. The rate of small cell lung cancer (SCLC) is decreasing as well [9]. Thus, in the United States the most likely clinical scenario is a patient with two lesions, both of which are adenocarcinoma. This is why simple demonstration of the same histologic type is not sufficient to classify the lesions as metastasis. (See "Pathology of lung malignancies".)

Advanced molecular testing such as DNA fingerprinting may be able to determine if the two lesions are separate primaries or the same lung cancer, but these are not available for routine clinical use and are only suggestive, but not definitive, in establishing relatedness. Comprehensive molecular testing has become the standard of care for patients with advanced NSCLC, and testing for programmed cell death ligand 1 and epidermal growth factor receptor (EGFR) mutations is standard for patients with resected NSCLC [10].

Some have suggested use of next-generation sequencing (NGS) panels to help distinguish MPLC from pulmonary metastasis, and to determine if the two lesions have different oncogenic drivers that would suggest two separate primaries. Comprehensive genomic profiling is used to investigate if a patient has metachronous or synchronous multiple primaries [11-13]. Several case series have investigated the role of NGS in distinguishing independent primary tumors from intrapulmonary metastases, and most of these have been from single centers, retrospective, and have included fewer than 50 patients [14-19]. These series suggest a role for NGS when histologic examination is uncertain and cannot determine if the two lesions are separate primaries. While the utility of this approach is greater when one of the tumors has a classic oncogenic-driver molecular alteration, it is potentially a more accurate diagnostic method that does correlate with prognosis [19].

A special clinical entity previously known as bronchioloalveolar carcinoma is now recognized as a spectrum ranging from adenocarcinoma in situ, to minimally invasive adenocarcinoma, to invasive adenocarcinoma with a range of growth patterns from lepidic predominant to mucinous [20] and represents an increasing proportion of lung adenocarcinoma in some but not all series [21,22]. (See "Pathology of lung malignancies", section on 'Adenocarcinoma'.)

This spectrum can frequently present as multifocal tumors (often referred to as multifocal adenocarcinoma) generally representing separate primary tumors rather than metastatic disease given their tendency to local rather than distant progression [21]. Multifocal disease has a characteristic appearance on computed tomography (CT), with lesions in varying states of progression from pure ground glass to partially solid to solid nodules, with individual tumors progressing over time at varying rates from very indolent over years to aggressive over months. As it may not be feasible to resect all the lesions, management of this scenario requires special consideration. (See 'Management' below.)

EPIDEMIOLOGY AND RISK FACTORS — Lung cancer has been causally linked to tobacco smoke in most cases, as well as to a wide range of other environmental risk factors. In addition, there is some evidence of a genetic contribution to the development of lung cancer for both smoking and nonsmoking-related lung cancer, especially in adenocarcinoma [23,24]. Tobacco and other carcinogens create a "field effect" in which multicentric cancers can arise in a benign contiguous tissue [25]. Importantly, the history of tobacco use predisposes patients to a variety of second cancers, and depending on the clinical presentation, a work-up for extrapulmonary second primary should be considered [26]. (See "Cigarette smoking and other possible risk factors for lung cancer".)

A literature review estimated that patients who underwent complete resection of a non-small cell lung cancer (NSCLC) have a risk of 1 to 2 percent per patient-year for the development of a second lung cancer [27-29]. Likewise, patients with small cell lung cancer (SCLC), who had been successfully treated, developed a second primary lung cancer at a rate of 6 percent per patient-year. In another study of patients with SCLC, the overall risk of a second cancer was 3.5 times higher compared with the general population [30].

Patients who continue to smoke have an increased risk of developing a second lung cancer compared with those who do not use tobacco [27,29-32]. The risk of a second primary lung cancer and its relationship to smoking were prospectively illustrated in a phase III chemoprevention trial, in which patients with resected stage I NSCLC were randomly assigned to selenium or placebo [33]. The rate of second primary lung cancers in the selenium and placebo arms was 1.62 and 1.30 per 100 person-years (p = 0.29). The overall survival was significantly different by smoking status. The rate of a second primary lung cancer or a recurrence among patients who were active smokers, former smokers, or never smokers was 30, 24, and 20 percent.

SYNCHRONOUS MPLC

Diagnostic and staging evaluation — The diagnosis of synchronous MPLC requires tissue to characterize both lung tumors. This is due to the fact that nodules in the ipsilateral lung are generally regarded as metastases. These are even more complex as multiple adenocarcinomas are reported to account for as much as 50 percent or greater of synchronous MPLC [34,35]. The information from histologic examination can provide the basis for characterizing some patients has having MPLCs.

The staging of a patient presenting with more than one primary lung cancer is complex and needs to be meticulous if potentially curative resection is being contemplated. Both magnetic resonance imaging (MRI) scan of the brain and a fluorodeoxyglucose positron emission tomography (FDG-PET) should be performed to evaluate for extrathoracic metastases.

Current guidelines for staging the mediastinum do not recommend invasive confirmation of mediastinal lymph node status for patients with peripheral stage IA non-small cell lung cancer (NSCLC) unless there is increased uptake on FDG-PET or increased size on computed tomography (CT) scan of the mediastinal lymph nodes [36,37]. This is based on the low pre-test probability of occult mediastinal lymph node involvement in this clinical situation.

However, there are insufficient data to determine the probability of mediastinal involvement in a patient with synchronous MPLC; therefore, invasive mediastinal staging cannot be omitted in patients for whom definitive resection is considered. Furthermore, when pathologic involvement of the mediastinal lymph nodes is present, it is more likely that a synchronous lesion represents an intrapulmonary metastasis than a second primary [5]. Thus, invasive staging of the mediastinum provides additional information about the potential for surgical resection and assists in clarifying whether the patient has two synchronous primaries or intrapulmonary metastases.

With differing histology in the MPLCs, treatment should be based upon providing the best long-term outcomes, with each tumor evaluated and treated irrespective of the other tumor. However, with similar histology in both tumors, this approach depends upon the certainty that the two lesions are indeed distinct.

Patients with multiple tumors with the same histology and N2 nodal involvement are generally treated as stage IV disease since a single malignant process is likely, but not definitively, responsible for all the lesions.

Management

Surgery — Surgery is a standard approach for treatment in patients with either synchronous or metachronous MPLC if there is sufficient pulmonary reserve after resection of more than one lesion. However, limited pulmonary reserve may require a patient to undergo a limited resection (eg, segmentectomy or wedge resection) of one or both lesions, or definitive non-operative local therapy. Hybrid approaches combining both surgical and nonsurgical (eg, stereotactic body radiation therapy [SBRT], ablation) modalities have been utilized. When a hybrid approach is utilized, the location of the tumors and the pulmonary reserves of the patient, as discussed below, are taken into consideration. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Surgical candidates'.)

Once the diagnosis of synchronous primary lung cancers has been established, the patient should be assessed for potential surgical resection of both lesions. Patients should undergo complete anatomic resection of both tumors, and a significant percentage of patients who undergo resection of both lesions will have mean long-term survival that exceeds 60 months [38-40].

There are no randomized trials confirming the efficacy of this approach; most of the data are retrospective, from single centers, and subject to both patient selection and publication bias. Furthermore, these analyses were performed before the widespread adoption of FDG-PET staging. Patients were also very carefully selected to undergo resection of both lesions based on comorbidities, pulmonary function, and anatomic location of the tumors. The location is quite important in light of the current definitions for the staging system. Two separate nodules on the same side with the same histology are now characterized as T4 and no longer considered metastatic disease.

In some instances, two synchronous tumors may have similar histology, and it may be impossible to determine whether or not these represent two primary tumors. In this situation, it may be appropriate to treat such patients as if these represent two primary lesions since that represents the "best case scenario," rather than to characterize them as having stage IV disease.

Non-operative local therapy — For patients who are not candidates for surgical resection of one or more lesions after appropriate cardiopulmonary work-up, other therapeutic options may achieve prolonged or definitive control of local disease. The data with these approaches are derived from patients with medically inoperable early-stage NSCLC.

Potential options include:

●Preferred: Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR). (See "Stereotactic body radiation therapy for lung tumors".)

●Conventional radiation therapy. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Nonsurgical candidates'.)

●Percutaneous image-guided tumor ablation. (See "Image-guided ablation of lung tumors".)

The advantages and limitations of each of these approaches for the treatment of lung cancer are discussed separately, as noted above.

For stage I NSCLC, prospective trials and population-based comparative analyses have found SBRT to be associated with higher local tumor control rates and overall survival compared with conventional radiation therapy or radiofrequency ablation, and similar compared with surgery in matched patient cohorts [41-46].

In patients with synchronous lesions, non-operative local therapy, especially SBRT, may have a role either to treat both lesions, or, in conjunction with surgery, in situations where the patient is thought to be unable to tolerate the surgery necessary to resect both primary lesions. The available data indicate the safety and potentially curative role of SBRT in MPLC, particularly in patients at high risk of surgical complications.

Seven retrospective studies of SBRT for MPLC with a total of 304 patients (with 10 to 101 patients in each study) treated with either SBRT to all lesions or a combination of surgery and SBRT for different lesions have been reported [47-53]. The majority of patients were medically inoperable. Median overall survival was 20 to 46 months. Two-year local tumor control rate was 81 to 99 percent. High-grade toxicities were rare. Patients with synchronous MPLC had lower overall and progression-free survival than those with metachronous MPLC.

For the special case of multifocal synchronous MPLC, especially the spectrum of adenocarcinoma formerly known as bronchioloalveolar carcinoma, resection of all lesions even using parenchyma-sparing techniques may not be feasible.

The highest-risk lesion(s) based on histologic grade or radiologic features (eg, growth, size and solid component, FDG uptake on PET) should be treated with definitive local therapy if possible, while lesions at low risk of becoming symptomatic (eg, small subsolid nodules with slow growth) may be observed until they demonstrate more aggressive radiologic features [54].

Because additional lesions may evolve to more aggressive growth and require treatment, use of parenchyma-sparing approaches is preferred, and stronger consideration of non-operative local therapy is warranted even as the initial approach. Definitive local therapy of additional lesions should be considered at the point they demonstrate potential for symptomatic progression (eg, subsolid nodules with accelerating growth or increasing solid component or increasing FDG uptake, even while small). Multifocal progression not amenable to definitive local therapy may warrant systemic therapy as for metastatic disease.

METACHRONOUS MPLC — Many patients who are successfully treated for non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) will develop a second primary lung cancer. In appropriately selected patients with metachronous NSCLC, surgical resection of the second primary can provide long-term survival [55]. Based on retrospective studies, the median time interval between the primary and the new lung cancer is 38 to 48 months, and approximately two-thirds of the tumors have the same histology [5,56].

One of the biggest challenges in treating a second primary is assessing if surgical resection is feasible. Approximately two-thirds of the metachronous lung cancers are resectable and approximately one-third of the patients who undergo a resection will have a limited resection [5]. However, limited resection (at least an anatomic segmentectomy) should be attempted in all cases. Segmentectomies have been shown to have similar outcomes to lobectomy in terms of recurrence-free survival, especially for tumors under 3 cm in size [57]. Additionally, segmentectomies can be safely performed either open or thoracoscopically and have significantly less impact on pulmonary function. A few small, single-institution studies have demonstrated both feasibility and superiority of repeat surgery compared with a non-operative approach for MPLC [56,58]. While there may be an elevated risk of morbidity and mortality within 90 days of surgery, the long-term outcomes are acceptable and superior when compared with similar study outcomes of non-operative intervention case series. The key point is that the patient must be able to tolerate the additional resection.

Patients with metachronous MPLC may also benefit from use of nonsurgical approaches, particularly with the reduced pulmonary reserve associated with an earlier resection when they are not candidates for further resection. (See 'Non-operative local therapy' above.)

ADJUVANT THERAPY FOR RESECTED NSCLC — There are no randomized trials to guide the use of adjuvant therapy in patients with MPLC. Therapies should be considered on a case-by-case basis with shared decision-making with the patient.

●Chemotherapy – Cisplatin-based adjuvant chemotherapy is the standard of care for patients with a single stage II or stage III non-small cell lung cancer (NSCLC) who have undergone a potentially curative resection. This approach is based upon results of phase III trials that have revealed an improvement in overall survival with chemotherapy compared with observation. The data for patients with stage I NSCLC are not definitive, but patients with no nodal involvement and with tumors greater than 4 cm may benefit. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Patients treated with initial surgical resection'.)

For patients with synchronous MPLC, the highest stage of tumor appears to be the best predictor of prognosis, and if the patient has resected stage II or III disease, then adjuvant chemotherapy is recommended [59]. The uncertain situation is when a patient has two synchronous or metachronous stage I NSCLCs. While patients with stage I NSCLC with MPLC may have a worse prognosis than patients with a single stage I NSCLC, the absolute benefit of adjuvant cisplatin-based chemotherapy is unclear. Clinicians should consider the size of the tumors, the patient's comorbidities, performance status, and preferences in deciding whether or not to use adjuvant chemotherapy in this situation.

●Immune checkpoint inhibitors – Immune checkpoint inhibitors have changed the management of advanced lung cancer [60]. These drugs are now being reported in small case series and reports for second primary lung cancers and MPLC [61-63]. However, multi-omic analysis can reveal genomic heterogeneity between tumors that may result in a distinctly different response to immunotherapy.

A phase III trial of adjuvant atezolizumab compared with standard of care in patients with resected NSCLC who received adjuvant chemotherapy revealed an improvement in disease-free survival (DFS) [64]. This therapy is available for patients with stage II or IIIA disease with a programmed cell death ligand 1 expression of ≥1 percent. Adjuvant pembrolizumab has shown promising preliminary results [65], but does not have regulatory approval. The clinical benefit in patients with synchronous primary lung cancers who underwent resection is unknown at this time since only patients with a single primary NSCLC have been enrolled.

●EGFR inhibitors in EGFR-mutant disease – A phase 3 trial of adjuvant osimertinib compared with standard of care in patients with stage IB to IIIA resected NSCLC with an epidermal growth factor receptor (EGFR) mutation revealed an improvement in DFS [66]. Similar to the adjuvant immunotherapy trials, the benefit in patients with synchronous primary lung cancers is not known at this time.

PROGNOSIS — Stage is still considered the most significant predictor of overall survival (OS) after surgical resection of MPLC. However, tumor size >2 cm and number of pack-years of smoking are associated with a statistically significant worse outcome. In a retrospective review of 285 patients with synchronous MPLC treated with surgical resection, the five-year disease-free and overall survival observed were 58.7 and 77.6 percent, respectively. On multivariate analysis of OS, male sex, symptomatic disease, and lymph node involvement were associated with a worse prognosis [67].

Metachronous primary lung cancers have a better prognosis than synchronous lung cancers, and the few retrospective studies that address only this cohort of patients revealed a five-year OS rate from time of diagnosis of the second primary, after surgical resection, of between 27 and 51 percent [68]. Another retrospective study of 161 patients revealed a five-year overall survival rate of 61 percent calculated from the time of the second resection [40,69].

The difference in prognosis between synchronous and metachronous MPLC has been difficult to determine due to the small sample sizes of many of the studies and variable definitions and follow-up. A meta-analysis of 22 relevant studies including almost 1800 patients investigated the overall survival differences between synchronous and metachronous MPLC [39]. Eleven studies analyzed overall survival for both synchronous and metachronous MPLC starting from the diagnosis of the first metachronous tumor (n = 580), and found patients with synchronous MPLC had a shorter overall survival. Interestingly, analysis of the nine studies that investigated overall survival starting from diagnosis of the second metachronous tumor (n = 1009) did not demonstrate a difference in overall survival. In the meta-analysis overall, neither histology nor position (unilateral versus bilateral) had an impact on survival. However, this study was limited and was not able to comment on impact of initial staging or nodal involvement [39]. Prior single-institution studies demonstrate that involvement of N1 or N2 lymph nodes was associated with increased mortality compared with no nodal disease (N0) [68,70-72].

A recent retrospective analysis of the Surveillance, Epidemiology, and End Results database from 2004 to 2015 of patients with metachronous non-small cell lung cancer analyzed outcomes. On multivariate analysis, age, time interval between lung cancers, and type of surgery for the first and second lung cancers were prognostic factors. Patients who underwent lobectomy for the first primary and sublobectomy for the second lung cancer had better outcomes, and a disease-free survival of 24 months was associated with a better outcome [73].

SURVEILLANCE — For patients who undergo a complete resection of a single non-small cell lung cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend computed tomography (CT) with or without contrast, history, and physical examination every 6 to 12 months for the first two years [74]. After two years, NCCN recommends a history and physical and low-dose non-contrast-enhanced CT scan annually. There are no available guidelines or recommendations due to a lack of data for follow-up of MPLC. However, for metachronous MPLC, existing guidelines for a single non-small cell lung cancer are reasonable. In patients with synchronous MPLC, a slightly more aggressive follow-up is recommended by the authors. Generally, the first year is every four months, followed by every six months for two years, and then annually starting at year 3. Smoking cessation advice, counseling, and pharmacotherapy are recommended for any patient who continues to use tobacco.

To date, clinical trials have not established a role of any agent in the prevention of lung cancer. (See "Chemoprevention of lung cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

SUMMARY AND RECOMMENDATIONS

●Multiple primary lung cancer (MPLC) is a relatively uncommon entity that seems to be increasing. This may be due to contemporary screening strategies and improvement in survival, which then leads to a concomitantly increased opportunity to develop new primary lung cancers.

●The increasing incidence of adenocarcinoma will lead to the clinical scenario where both lesions will have the same histology. Multifocal adenocarcinoma is a separate clinical entity that requires special consideration. (See "Management of stage III non-small cell lung cancer", section on 'Multiple tumor nodules'.)

●Treatment requires careful coordination and assessment in a multidisciplinary team, which includes a careful review of imaging studies, pathology, and assessment for surgical resection by a thoracic surgeon. All patients with MPLC should be approached with a curative intent, as a select group of patients will experience long-term survival.

●Stage is the most significant predictor of overall survival after resection of MPLC.

●Surgery currently is the standard option when feasible. Standard principles of surgical resection to include anatomic resection with either lobectomy or segmentectomy are preferred. (See 'Surgery' above.)

●In those patients that are high-risk surgical candidates after appropriate cardiopulmonary testing or who are likely to require treatment for additional lesions, one or potentially multiple lesions can be considered for definitive non-operative local therapy, particularly stereotactic body radiation therapy. (See 'Non-operative local therapy' above.)

●In those patients with resected synchronous primaries, the decision to give adjuvant platinum-based chemotherapy, targeted therapy, or immunotherapy should be based upon the lesion with the highest stage. For patients with either synchronous or metachronous stage II or III non-small cell lung cancer, adjuvant cisplatin-based chemotherapy should be considered based on the survival benefit observed in patients with a single resected lesion. (See 'Adjuvant therapy for resected NSCLC' above.)

●Studies have revealed an improvement in disease-free survival with adjuvant atezolizumab in patients with resected stage II or III disease and programmed cell death ligand 1 expression ≥1 percent and adjuvant osimertinib for patients with an epidermal growth factor receptor (EGFR) mutation. These therapies should be considered on a case-by-case basis with shared decision-making with the patient.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Billy W Loo, Jr, MD, PhD, who contributed to an earlier version of this topic review.