Metachronous Multiple Lung Cancers Research Articles

P06.01 Therapeutic Strategies for Metachronous Multiple Primary Lung Cancer

It is not uncommon to encounter metachronous primary lung cancer after surgical treatment along with the increase in the elderly patients. In consideration of increasing number of such patients, it is necessary to take various treatment strategies. Method: In order to establish a treatment strategy for multiple lung cancer, we retrospectively examined multiple lung cancer cases operated for primary lung cancer in our department from January 2013 to December 2018, and the future treatment strategy was examined. In order to establish a treatment strategy for multiple lung cancer, we retrospectively examined multiple lung cancer cases operated for primary lung cancer in our department from January 2013 to December 2018, and the future treatment strategy was examined. Of 821 patients who underwent surgery for primary lung cancer, 60 were multiple lung cancers, 31 were synchronous multiple lung cancers, and 29 were metachronous multiple lung cancers. Among the cases of metachronous multiple lung cancer, 27 cases had undergone lobectomy or more in the first operation, 1 case of segmental resection, and 1 case of partial resection. As for the treatment of secondary lung cancer lesions, 20 lesions were performed surgery (lobectomy; 1, segmental resection;5, partial resection; 14), 6 lesions of photodynamic therapy (PDT), and 3 lesions of SBRT. Among the surgical cases, there were 3 cases on the same side as the first cancer and 17 cases on the opposite side. The three cases underwent partial resection. Among 17 patients, postoperative home oxygen therapy was introduced in 2 patients. Regarding the prognosis, three patients who had surgical resection, died of recurrence of the first lesion. Two of the six PDT patients died of recurrence of the first lung cancer and one died of other disease. All three patients who underwent SBRT are alive without recurrence. If early detection and early diagnosis are made as a treatment strategy for metachronous multiple lung cancer, it may be possible to preserve lung function by reducing surgery or SBRT, PDT, and to cure without damaging the quality of life.

P2.16-28 Retrospective Analysis of Patients with Previous Extrathoracic Malignancies After Resection of Non-Small Cell Lung Cancer

The number of patients with previous malignancies has increased because survival time is prolonged in various malignancies. Therefore, opportunities to consider surgical indications for non-small cell lung cancer (NSCLC) patients with previous malignancies are increasing. The aim of the study is to compare the backgrounds and prognosis of NSCLC patients who had the history of previous extrathoracic malignancies with no other cancer history. Our institutional database of patients after curative resection of NSCLC from 2006 to 2013 was reviewed. Patients with synchronous or metachronous multiple lung cancer were excluded. Clinicopathological features of these patients and information about survival and recurrence were collected from the electronic medical record. Overall survival (OS) and recurrence-free probability (RFP) were estimated using the Kaplan-Meier method. In a total of 249 patients, 49 (19.7%) had previous extrathoracic malignancies. The number of previous extrathoracic malignancies was 1 in 44 patients, 2 in 3 patients and 3 in 1 patient. Sixteen patients had colorectal cancers among previous extrathoracic malignancies, 10 patients had gastric cancers and 5 had hematopoietic neoplasms. If patients with previous extrathoracic malignancies were compared to those without, the median age was 69.5 vs. 65.5 (p=0.015), male sex was 71.4% vs. 66.5% (p=0.506), average of Brinkman index was 914.2 vs. 709.7 (p=0.127) and average of serum level of carcinoembryonic antigen was 5.4 ng/mL vs. 7.5 ng/mL (p=0.506). Pathologically, stage 0 and I NSCLC account for 73.5% of patients with previous extrathoracic malignancies and 66.0% of those without it (p=0.311). The 5-year OS was 70.3% vs. 79.1% (p=0.422) and the 5-year RFP was 58.9% vs. 67.7% (p=0.223). Patients with previous extrathoracic malignancies are significantly older than those without previous extrathoracic malignancies. Patients with previous extrathoracic malignancies had relatively earlier stage NSCLC. The OS and RFP also tended to be worse in patients with previous extrathoracic malignancies. Further study is needed to consider surgical indication for NSCLC with previous extrathoracic malignancies.

Clinicopathologic Characteristics and Prognosis of Patients With Non–Small Cell Lung Cancer Who Undergo Pulmonary Segmentectomy

This study retrospectively investigated the clinical characteristics and prognosis of the non–small cell lung cancer (NSCLC) patients who underwent segmentectomy as either intentional or passive limited surgery. The subjects included in this study comprised 72 patients who underwent segmentectomy at our hospital. There were 23 patients who underwent intentional segmentectomy. The histologic type was adenocarcinoma in all of these patients. Regarding the tumor size, 9 tumors were 1 cm or less in diameter, 13 were 1.1 to 2 cm, and 1 was 2.5 cm. All patients who underwent intentional segmentectomy were alive without any recurrence as of the last follow-up examination. A passive segmentectomy was performed for 49 patients. The reasons for passive segmentectomy were due to the presence of metachronous multiple lung cancer in 14 patients, synchronous multiple lung cancer in 9 patients, age above 80 years in 12 patients, reduced pulmonary function in 8 patients, and moderate to severe cardiovascular disease in 4 patients; another 2 patients were receiving treatment for another primary cancer. The 5-year survival rate of the patients who underwent passive segmentectomy was 69.8%. There was no postoperative mortality in either of the groups. This study showed that all of the patients who underwent intentional segmentectomy were alive without any recurrence, thus suggesting that the procedure is associated with sufficient oncologic efficacy, along with preservation of the lung function. The passive segmentectomy was a feasible procedure and was an alternative procedure with an acceptable overall survival rate in high-risk patients with underlying medical comorbidities.

Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis

In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer‐related oncogenes using next‐generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

Abstract 3680: Comparative mutational evaluation for multiple lung cancer by multiplex oncogene mutation analysis

Abstract [Background] In the treatment of synchronous or metachronous multiple lung cancer (MLC), determination whether multiple primary lung cancer (MP) or intrapulmonary metastases (IM) is very important to make an appropriate management. Clinical or pathological diagnoses have been adopted to distinguish whether MLC were MP or IM, however, the accuracy of these approaches seemed to be insufficient. On the other hand, recent evolution of high-throughput sequencing made it possible to perform comprehensive gene mutation analysis in cancer cells. The aims of this study were to investigate mutational profiles of synchronous or metachronous MLC, and to compare multiplex gene mutation analysis of MP or IM among paired tumors with clinical or pathological evaluations. [Methods] We performed targeted sequencing for 20 lung cancer related oncogenes using next-generation sequencing technology in 82 tumors from 37 patients (18 patients with synchronous MLC and 19 patients with metachronous MLC) who underwent surgical resection in our department from July 2002 to April 2013. Then, classification of MP or IM was made by clinical, pathological, and gene mutational evaluation. [Results] Among paired tumors, matching of mutation was observed in 20 (54%) cases (nine cases with completely matched and 11 cases with partially matched), which were diagnosed as IM by mutational evaluation. In pathologically suggested IM cases (n=7), six (86%) patients were interpreted as IM by mutational evaluation, and most of them (n=5) had multiple matched mutations, which suggested the clonality between paired tumors strongly. In pathologically suggested MP cases (n=17), the mutational diagnosis was discordant in eight (47%) patients. Among these cases, four paired tumors had multiple matched mutation, suggesting the pathological diagnosis in these cases might be incorrect. In addition, careful interpretation was required when the paired tumors harboring frequent mutation including TP53 or EGFR because such mutation may match accidentally. [Conclusion] Our findings suggest that multiplex mutational analysis of synchronous or metachronous MLC could complement the pathological diagnosis in differentiation whether MP or IM. In the cases with pathologically equivocal or those with discordant between pathological diagnosis and mutational evaluation, the frequency and the number of matched mutation may be helpful for the differentiation. Citation Format: Yuta Takahashi, Kazuhiko Shien, Shuta Tomida, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Takahiro Yoshioka, Hidejiro Trigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka. Comparative mutational evaluation for multiple lung cancer by multiplex oncogene mutation analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3680.

A Case of Metachronous Multiple Lung Cancers Coexistent with Pulmonary Non-tuberculous Mycobacteriosis

A Case of Metachronous Multiple Lung Cancers Coexistent with Pulmonary Non-tuberculous Mycobacteriosis

P2.01-018 Risk Factors in Patients with Pathological N1 or N2 Non-Small Cell Lung Cancer

Pathological (p) N1 or N2 non-small cell lung cancer (NSCLC) patients may experience poor prognosis despite complete resection; therefore, adjuvant chemotherapy is recommended for them. In this study, we investigated the risk factors for pN1 or N2 NSCLC. From March 2005 to December 2015, we retrospectively reviewed 93 patients with completely resected pN1 or N2 NSCLC. Patients with synchronous or metachronous multiple lung cancer, malignancies from other organs, or who received neoadjuvant chemoradiotherapy were excluded. Clinicopathological factors analyzed included: age, sex, serum carcinoembryonic antigen levels, surgical procedures, histology, size of invasive tumor, pathological N status, pleural invasion, lymphatic invasion, vascular invasion, and histological grade. Univariate and multivariate analyzes of disease-free survival and overall survival were conducted. The study group comprised 93 patients (64 men, 29 women; age range: 38–86 years; mean: 68±9.9 years). The median follow-up period was 35.1 months. The preoperative serum carcinoembryonic antigen level was elevated in 36 patients. Complete resection was performed in all patients, comprising pneumonectomy in two patients (including sleeve pneumonectomy), bilobectomy in three, and lobectomy in 87 (including lobectomy with bronchoplasty or resection adjacent organs). Adenocarcinoma, squamous cell carcinoma, and other histology were observed in 59, 22, and 12 patients, respectively. The maximum diameter of invasive diameter was >30 mm in 39 patients and ≤30 mm in 54. There were 52 patients with pN1 and 41 with pN2. Forty-four were with pleural invasion, 52 with lymphatic invasion, and 48 with vascular invasion. Multivariate analysis showed histology to be an independent factor for recurrence, whereas older age (>70 years), pleural invasion, and adjuvant chemotherapy were independent factors for poor survival. There were 24 patients with no adjuvant chemotherapy, 10 could not receive it because of poor postoperative performance status, and 3 were ineligible because of older age. The 5-year overall survival in patients with adjuvant chemotherapy was 61.8%, compared with 23.8% for those without (p =0.002). Older age, pleural invasion, and adjuvant chemotherapy were found to be independent factors for poor survival in pN1 or N2 NSCLC. Adjuvant chemotherapy is a potential consideration for pN1 or N2 patients. Surgery to maintain performance status may be useful in relation to undergoing adjuvant chemotherapy.

SC02.01 Multiple Primary Lung Cancers Versus Lung Metastases: Pathological Differential Diagnosis

The pathological differential diagnosis of in a patient with synchronous multiple tumors has a similar thought process for classic morphology as for DNA analysis. Metachronous multiple lung cancers are not discussed here, as the provided title implies a clinical situation at moment in time. In the end of the text the usefulness of clinical context is mentioned.1–5 Morphology In the setting of obvious metastatic dissemination, histologic appearance is generally conserved. This implies that most metastases look alike and in most instances also have a similar morphologic appearance as the primary tumor. However, dedifferentiation occasionally occurs in metastases. Thus it is reasonable to conclude that lesions of different histological types, e.g. squamous cell and adenocarcinoma, are two separate primary cancers. Recently, it was suggested that differences in a comprehensive histologic assessment may provide an argument for separate primary cancers. However, resection specimen analysis is required for this assessment, making this approach only useful in about 15-20% of the cases. Moreover, an evidence based data set supporting comprehensive histologic assessment is currently lacking. Reproducibility has to be taken into account.6 In contrast to different morphological types, in case of two tumors with similar morphology a conclusion for same lineage (primary tumor- metastases relation) or different lineage (two primary tumors) is not easy to reach. The reason for this is that within an individual the genetic predisposition and etiologic factors are the same and may lead to separate tumors with the same morphology, which may still represent two lineages (thus two primary tumors) or alternatively, the same morphology in metastatic setting is one lineage. In case of multiple adenocarcinoma in-situ lesions, they are assumed to be separate primaries. In summary, in comparing two tumors differences in morphologic types is conclusive for second primary tumors, but demonstration of the same morphology is not sufficient for lineage analysis. DNA changes Demonstration of specific driver mutations by widely available PCR sequencing techniques may have use in establishing lineage.7In case of different driver mutations between two tumors, this obviously provides a strong argument for two primary (lung) cancers. However the frequency of discordant driver mutations is not so high. Noteworthy is that the demonstration of different passenger mutations does not have any use for lineage determination. In case of equal driver mutations a conclusion about lineage is not easy to reach.8,9 Not only because the genetic predisposition and etiologic factors are the same, but also because in certain genes hotspot mutations occur. Thus simple demonstration of the same mutation does not provide definite evidence for lineage analysis. On this matter more research is needed with posterior probability analysis involving a relevant number of similar mutations. A detailed genetic assessment such as in comparative genomic hybridization (CGH) may have greater discriminative power but has been used in only a few small studies.10 In array CGH the number of data points is orders of magnitude greater than in mutation analysis. Array CGH encompasses the predisposition and etiologic factor related copy number variations (CNV) as well as lineage specific CNV. In this sense comparison of exact breakpoints in gene rearrangements is useful. Although the data are limited as the assessment was in the past complex, nowadays array CGH in the form of shallow sequencing can reliable be performed on small biopsies as well. To which extend NGS with a large mutation panel may be useful remains to be seen. In summary, different driver mutations is conclusive for second primary tumors, but demonstration of the same driver mutation is not sufficient for lineage analysis. Adding clinical context provides interesting arguments. 1) Imaging may show multiple ground glass opacities (mGGO) and lack of enlarged lymph nodes. Although the morphology may be similar (lepidic pattern with AIS, MIA, Invasive adenocarcinoma) the mGGO lesions are considered to be separate primaries. In case of part solid component the morphological equivalent is usually infarction (=benign) or invasive cancer. 2) Imaging may show multiple consolidations (pneumonic type) with mostly the morphological correlate of invasive mucinous adenocarcinoma. 3) Abundance of nodular lesions, provides an argument for metastases (although rare exceptions exist, e.g. DIPNECH, Carney’s triad), while lack of nodal or systemic metastases provides an argument of two primary lung cancers. 4) Clinical follow-up is in hindsight only partly useful: lack of nodal or systemic metastases provides an argument of two primary lung cancers, while presence of local and/or distant metastases may be due to one of the two or both lung cancers. If morphological and/or DNA analysis provides differences between two tumors it is relatively easy to establish that these pulmonary foci of cancer are separate primary tumors. Many commonly used characteristics are associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.

A Case of Metachronous Multiple Lung Cancers with Large Cell Carcinoma with Neuroendocrine Morphology and Adenosquamous Carcinoma

A Case of Metachronous Multiple Lung Cancers with Large Cell Carcinoma with Neuroendocrine Morphology and Adenosquamous Carcinoma

New Aspects of the Clinicopathology and Genetic Profile of Metachronous Multiple Lung Cancers

For treatment decisions and prognostic applications, we evaluated p53/epidermal growth factor receptor (EGFR) somatic aberrations in metachronous multiple lung cancers to differentiate multiple primary lung cancers (MPLCs) from pulmonary metastases. The current criteria to differentiate MPLCs from metastases are based on the histologic type and onset interval and do not incorporate genetic analysis. The genetic background of MPLCs remains unclear. Ninety-seven metachronous multiple lung cancers were identified to investigate somatic mutations in p53 and EGFR. Mutational analysis of p53 and EGFR was performed on DNA extracted from paraffin-embedded tumors. A high frequency of somatic mutations in p53 (44.3%; 43/97) and/or EGFR (51.5%; 50/97) resulted in a high discrimination rate of tumor clonality (77.3%; 75/97) in metachronous multiple lung cancers. Of the 97 cases, 25 cases (33.3%) and 50 cases (66.7%) were assessed as having the same clonality (SC) and different clonality (DC), respectively. Notably, DC was commonly observed among tumors of the same histologic type (60.7%; 37/61), which further supported the carcinogenic theory of field cancerization. Multivariate analysis revealed that a first primary tumor of 3 cm or smaller (5-year survival: 92.7%; P = 0.001) and a limited resection of the latest tumor (5-year survival: 96.0%; P = 0.016) were 2 independent predictors of favorable prognosis. Because most metachronous tumors of the same histologic type have different clonal origins, clonality assessment is essential to differentiate MPLCs from metastases. We recommend limited resection as the treatment of choice to achieve long-term survival in MPLCs patients with tumors of 3 cm or smaller.

Early hilar lung cancer — risk for multiple lung cancers and clinical outcome

In early hilar lung cancer patients, multiple lung cancers frequently develop. The clinical outcome of such patients were studied. A total of 91 patients, 88 men and three women, who were endoscopically diagnosed with early hilar lung cancer were studied retrospectively. Surgery was performed in 46 patients, while organ-sparing treatment, including photodynamic therapy (PDT), Nd–YAG (neodymium–yttrium, argon, garnet) laser vaporization, and radiotherapy, were done for 45 patients. During follow-up, newly developed lung cancers and/or malignancies in other organs were recorded. The average smoking index (cigarettes per day×years) was 1040. Synchronous and/or metachronous multiple lung cancers developed in 26/91 patients (28.6%). Malignancies in other organs were found in 12/91 (13.2%). The smoking index of patients with multiple lung cancers was significantly higher than for other patients. The overall 5 year survival rate was 70.7% in all patients, 76.0% in the surgery group, and 64.4% in the nonsurgery group. The lung cancer-specific 5 year survival rate was 89.8% in all patients, 89.3% in the surgery group, and 90.5% in the nonsurgery group. Early hilar lung cancer frequently accompanies other lung cancers or malignancies in other organs. A favorable prognosis can be obtained with organ-sparing treatment.