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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 50-54

Non-small-cell lung cancer metastasis to unusual sites: A retrospective case series


1 Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India
2 Department of Radiology, Tata Medical Center, Kolkata, West Bengal, India

Date of Submission08-Dec-2020
Date of Decision23-Feb-2021
Date of Acceptance01-Mar-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Sandip Ganguly
Department of Medical Oncology, Tata Medical Center, 14 Mar EW Arterial Road, Newtown, Kolkata - 700 160, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_359_20

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  Abstract 


Background: The majority of all lung cancers are non-small-cell lung cancers (NSCLCs). They usually spread to the pleura, brain, adrenal gland, lungs, liver, and bones. However, clinical data for NSCLC metastasizing to unusual sites are sparse in the literature.
Objectives: We aimed to assess the pattern of metastases to unusual sites and evaluate the clinicopathological characteristics, treatment details, and outcomes of patients with NSCLC.
Materials and Methods: This retrospective case series was conducted in the Department of Medical Oncology of a tertiary cancer center in Eastern India between May 2011 and December 2018. Patients with cytologically or biopsy-proven treatment-naive stage IV NSCLC were included in this audit. Sites other than the pleura, brain, adrenal gland, lung, liver, and bones were considered as unusual sites of metastases. Clinicopathological characteristics, site of metastases, treatment details, and outcomes were recorded. Data were described using descriptive statistics, survival was estimated using the Kaplan–Meier analysis, and log-rank test was used to determine survival estimates.
Results: A total of 1549 patients with metastatic NSCLC were registered, of which 121 (7.8%) had metastases to unusual sites. The median age of the cohort was 72 years (range, 19–87 years), and the male:female ratio was 7:1. The most common site of unusual metastasis was the skin with soft tissue, followed by the kidney; metastasis to these sites was seen in 31 (2%) and 26 (1.6%) patients, respectively. Systemic chemotherapy was given to 67 (55.3%) patients. At a median follow-up of 11.2 months (95% confidence interval [CI], 6.8–17.5), the median progression-free survival of the cohort was 5.9 months (95% CI, 3.8–9.1).
Conclusions: In <10% of the patients, NSCLC can spread to unusual sites, most commonly to the skin/soft tissue and the kidney. A detailed discussion with the radiologists is necessary to distinguish NSCLC that has metastasized to unusual sites from second primary tumors and to avoid unnecessary tissue biopsies from these areas.

Keywords: Lung cancer, metastasis, non-small-cell lung cancers, unusual sites, NSCLC


How to cite this article:
Ganguly S, Ghosh J, Gehani A, Basu A, Chatterjee M, Dabkara D, Biswas B. Non-small-cell lung cancer metastasis to unusual sites: A retrospective case series. Cancer Res Stat Treat 2021;4:50-4

How to cite this URL:
Ganguly S, Ghosh J, Gehani A, Basu A, Chatterjee M, Dabkara D, Biswas B. Non-small-cell lung cancer metastasis to unusual sites: A retrospective case series. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Oct 21];4:50-4. Available from: https://www.crstonline.com/text.asp?2021/4/1/50/312090




  Introduction Top


As per the GLOBOCAN 2020, lung cancer is the most common cause of cancer-related deaths worldwide.[1] Usually, lung cancer is diagnosed at a late stage when the disease has spread to distant organs.[2] The most common type of lung cancer is non-small-cell lung cancer (NSCLC),[3] with adenocarcinoma being the most common histological subtype.[4] The treatment paradigm of NSCLC ranges from systemic chemotherapy to molecular targeted therapies and more recently, the immune checkpoint inhibitors. With newer therapies, there has been a marked improvement in disease control and survival.[5] NSCLCs typically metastasize to the brain, pleura, adrenal gland, liver, bones, pericardium, and lymph nodes.[6] Sites other than these are considered unusual, and metastasis of NSCLC to these unusual sites is very rare.

There is a paucity of data on NSCLC metastasis to unusual sites.[7] There is confusion regarding the diagnosis, optimal treatment modalities, and prognosis of patients with NSCLC that has metastasized to unusual sites. This may lead to unnecessary investigations and delay in treatment, thereby affecting the outcomes. Detailed discussion with the radiologists with consideration of clinical symptoms may clinch the diagnosis and prevent unnecessary procedures and treatment delays.

We, therefore, performed a study to evaluate the clinical features, treatment, and outcomes of our patients with NSCLC metastatic to unusual sites.


  Materials and Methods Top


General study details

This is a retrospective case series conducted in the Medical Oncology Department of a tertiary cancer center in Eastern India between May 2011 and December 2018. Given the retrospective nature of the analysis, the Institutional Ethics Committee permitted the study without the need for formal approval (EC/WV/TMC/01/21), and the need to obtain written informed consent from the participants was waived off. This study was not registered in a public clinical trials registry. The study was conducted in accordance with the ethical principles in the Declaration of Helsinki and the Indian Council of Medical Research guidelines for clinical research. No funding was obtained to conduct this retrospective audit.

Participants

Patients with cytologically or biopsy-proven treatment-naive stage IV NSCLC who had metastasis to unusual sites alone or in addition to common sites were included in this study. Unusual sites of metastasis were sites other than the brain, pleura, adrenal glands, liver, bones, pericardium, and lymph nodes. Patients with inadequate work-up, non-metastatic disease, and those who did not undergo treatment were were excluded from the analysis.

Variables

Our primary objective was to analyze the pattern of metastases to unusual sites in patients with advanced NSCLC. Our secondary objectives were to assess the clinicopathological characteristics, treatment details, and outcomes of these patients.

Study methodology

Data for this retrospective case series were obtained from the electronic medical records. The diagnosis of metastasis to unusual sites was based on the clinical, pathological, and radiological investigations. All patients had undergone imaging modalities like computed tomography (CT) scan of the thorax and whole abdomen or positron emission tomography/CT. Magnetic resonance imaging of the brain was performed to rule out brain metastasis in patients who initially presented with localized disease or had any neurological symptoms at baseline. The diagnosis of metastases to unusual sites based on imaging modalities was confirmed by the radiologists depending on the extent of the metastatic disease on imaging, and the similarity in terms of the morphological characteristics of the metastatic lesions. In cases of clinical and radiological discordance, a tissue biopsy was attempted from the unusual site of metastasis to rule out a second primary tumor. In case of similar histological morphology of the second site, appropriate immunohistochemical examination was performed along with a review of the primary biopsy to differentiate metastasis from a second primary tumor. Diagnosis of NSCLC was made based on the results of suitable immunohistochemical studies performed on the biopsied tissue. The commonly used immunohistochemical markers were thyroid transcription factor 1, napsin, and p63. Testing for mutations in the epidermal growth factor receptor (EGFR) gene by amplification refractory mutation system real-time polymerase chain reaction and rearrangements in the anaplastic lymphoma kinase (ALK) gene either by immunohistochemistry (D5F3 clone) or fluorscence in situ hybridization (FISH) was performed for tumors with adenocarcinoma histology as well as for those with squamous histology, if the patients were women or non-smokers. In selected cases, ROS1 testing by FISH was also done for patients with adenocarcinoma histology.

Treatment and response evaluation

Post diagnosis, the cases were discussed in the multidisciplinary tumor board of the disease management group in the hospital. Patients were administered systemic treatment if they had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score between 0 and 2 with normal organ functions. The chemotherapy regimen consisted of pemetrexed and carboplatin for tumors with adenocarcinoma histology and carboplatin and paclitaxel/gemcitabine for tumors with squamous histology. For patients with EGFR-mutant adenocarcinomas that were sensitive to oral tyrosine kinase inhibitors (TKIs), gefitinib or erlotinib was used. For ALK-positive tumors, crizotinib or ceritinib was used if affordable by the patients, and for ROS1-positive tumors, crizotinib was used. Patients with very poor PS (ECOG PS ≥3) received best supportive care. Patients who were compliant with treatment were assessed periodically for response by radiological imaging. Complete response, partial response, stable disease, and progressive disease were defined according to the response evaluation criteria in solid tumors (v1.1), wherever applicable.[8]

Statistics

As this was a retrospective case series, we did not calculate a formal sample size; all patients who fulfilled the eligibility criteria within the time frame of the study were included. The clinical and demographic characteristics of the patients were analyzed using descriptive statistics. Survival was estimated using the Kaplan–Meier method, and a log-rank test was used to determine survival estimates.[9] Patients who either missed their scheduled hospital visits for more than a month or could not be contacted telephonically were deemed lost to follow-up. They were censored on the date of the last contact/follow-up. Patients who were alive as of May 14, 2020, were censored for overall survival (OS) analysis. The COX proportional hazard model was used to assess the differences between the outcomes for the unusual sites of metastases. A stepwise multivariate Cox regression analysis was performed to identify the predictors of outcome. Factors with statistical significance (P < 0.05) in the univariate analysis were entered into the multivariate analysis. Progression-free survival (PFS) was calculated from the date of primary diagnosis to the date of clinical or radiological disease progression. OS was calculated from the date of diagnosis to the date of death from any cause. Patients who were lost to follow-up or had abandoned treatment were censored in the analysis of the PFS and OS. The median follow up was calculated for only the surviving patients. Patients who received at least one cycle of chemotherapy were included in the modified intention-to-treat survival analysis. This was done to capture the real-world picture of treatment outcomes in a developing country. STATA/SE 11.0 (StataCorp, College Station, Texas, USA) was used for statistical analysis.


  Results Top


During the study period, a total of 1549 consecutive patients with metastatic NSCLC were registered in our department. Of these, 121 (7.8%) patients had metastases to unusual sites. There were 62 (51.2%) patients who received at least one cycle of chemotherapy and were included in the survival analysis [Figure 1]. The baseline characteristics of the patients are shown in [Table 1].
Figure 1: Recruitment flow chart for the retrospective case series of patients with metastatic non-small-cell lung cancer metastatic to unusual sites

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Table 1: Baseline characteristics of the patients (n=121)

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The median age of the patients was 72 (range 19–87) years, and the cohort comprised 106 (82%) men. Consumption of tobacco-related products was reported in 85 (71.3%) patients. Adenocarcinoma was the most common histology and was seen in 88 (72.7%) patients. A total of 114 (94.4%) patients had more than one site of metastasis. The median number of sites of metastases was 3 (interquartile range, 3–5). In 93 (76.9%) patients, the disease was diagnosed using a tissue biopsy either from the primary tumor in the lung or the most accessible metastatic site. A tissue biopsy was obtained for diagnosis from the unusual site in 17 (14.6%) patients to confirm if the lesion had metastasized from the lung primary. In addition, an EGFR mutation was detected in 21 (24%) out of the 88 patients with adenocarcinoma. Two patients were noted to be ALK-positive, and only one patient had ROS1-positive NSCLC.

The skin and soft tissue were the most common sites of unusual metastasis; metastasis to these sites was observed in a total of 31 patients, i.e., 2% of the total cohort of patients with metastatic NSCLC. The second most common site of unusual metastasis was the kidney, which was observed in 26 (1.6%) of the total of 1549 patients [Table 2]. Of the patients with unusual metastases, metastasis to the brain was observed in only 14 (12%) patients.
Table 2: Unusual sites of metastases in the patients with metastatic non-small-cell lung cancer (n=1549)

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Only 67 (46.8%) patients received at least one cycle of systemic therapy. At a median follow-up of 11.2 months (95% confidence interval [CI], 6.8–17.5), the median PFS for the entire cohort was 5.9 months (95% CI, 3.8–9.1) [Figure 2]. The median PFS for patients with tumors of squamous histology was 3.8 months (95% CI, 0.9–6.7) [Figure 1S]. For patients with targetable mutations, who were treated with oral TKIs the median PFS was 16.8 months (95% CI, 8.7–23.2) versus 4.2 months (95% CI, 2.8–7.1) for those whose tumors did not have any actionable mutations [Figure 2S] and [Figure 3S]. None of the patients received immunotherapy. The median OS of the entire cohort was 22.6 months (95% CI, 10.9–NR). The Cox univariate analysis did not reveal any statistically significant correlation between the unusual sites of metastasis and the PFS [Table 1S].
Figure 2: Kaplan–Meier survival curve for the median progression-free survival of the entire cohort

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  Discussion Top


In our study, a total of 121 (7.8%) patients with metastatic NSCLC had metastases to unusual sites. The most common unusual sites were skin and soft tissue followed by the kidney and muscle. The most common histology was adenocarcinoma. Lung cancer can spread both by lymphatic and hematogenous routes. Autopsy studies have shown that it most commonly spreads to the liver (34.3%), adrenal gland (32.6%), bones (14.9%), and brain (12%).[6] The incidence of lung cancer spreading to unusual sites is around 5%.[7] However, there is limited literature, mostly in the form of case reports, on the unusual sites of metastasis for lung cancer.[7],[10],[11],[12],[13],[14],[15],[16]

Niu et al. and Neffati et al. both reported adenocarcinoma as the most common histological type [Table 3].[7],[14] The median age of the patients in Niu et al.'s study was 58 years,[7] which is less than that in our cohort (72 years). Scatena et al.'s study showed a predilection of male patients for metastasis to unusual sites,[17] and these findings are similar to those from our study. Metastasis to unusual sites is often reported in the later stages of the disease, however, in our series, all the patients had metastasis to unusual sites at the time of initial diagnosis. The outcomes of patients with synchronous and metachronous metastases to unusual sites were found to be similar.[7] The reasons for their similar outcomes cannot be explained fully, given the limited availability of literature.
Table 3: Comparison with other studies

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There is a dearth of information about the molecular profile of patients with lung cancers with metastasis to unusual sites. Moreover, there is limited information about the survival outcomes of these patients. Only one study has shown that patients with metastases to unusual sites have a poorer survival compared to those who do not.[7] This can be postulated to result from the greater disease burden of patients with metastases to unusual sites. Another hypothesis is that metastatic cancer cells that spread to hostile unusual environments have intrinsic resistance to standard chemotherapeutic agents, but this is not well-proven.

The concept of metastatic spread to certain organs is based on the “seed and soil hypothesis.”[18] The tumor cells, designated as the “seed,” release cytokines and proteins which interact with the microenvironment of the distant sites, designated as the “soil.” A proper interaction between these cytokines and the microenvironment causes the tumor cells in circulation to home into the distant sites causing metastasis. However, some sites such as the skin, spleen, and muscles are not favorable for distant metastasis. The reasons could be the decreased cardiac output to these organs, especially the skin; presence of immune cells; immune surveillance in organs such as the spleen; or the presence of a nonconducive environment due to the low pH or anaerobic metabolism, as is the case of the muscles. Because of the spread to unusual sites, it can be difficult to differentiate a metastatic lesion from a second primary tumor. Radiologists play a vital role in resolving this confusion. The pattern of distribution of the metastatic lesions, morphological similarity between the sites of metastases, and in extreme cases, arterial and venous phase studies help to clinch the diagnosis of metastasis to unusual sites. Only in cases where the metastasis is solitary or it is difficult to delineate the nature of the lesion, an additional tissue biopsy from the unusual sites is required to confirm the metastatic disease.

Our study had some limitations, including its retrospective design. Many patients did not take the prescribed treatment, and several of them abandoned treatment midway. Moreover, as the survival data for our lung cancer cohort are still immature, we did not compare the outcomes of our study population with those of the patients who did not have metastasis to unusual sites. Nevertheless, we made an attempt to assess the prevalence of metastases to unusual sites in patients with advanced NSCLC, which is largely unreported in the literature. A noteworthy aspect of our study is that standard imaging and diagnostic modalities were used for disease staging in all the patients in our cohort. Moreover, because of the robust electronic medical records facility of our hospital, all the patients' data were recorded accurately, without missing data.


  Conclusions Top


Lung cancer can spread to unusual sites in 7.8% of patients, most commonly to the skin and soft tissues. It can be difficult to differentiate metastasis to unusual sites from second primary tumors. In case of discordance or high clinical suspicion of a second primary tumor, diagnosis using a tissue biopsy should be attempted from one of the unusual sites. Therefore, it is essential to familiarize oncologists with the concept of metastasis to unusual sites and this can be done with the help of radiologists and pathologists.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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