Abstract
Background/Aim: Spontaneous regression (SR) of cancer, which indicates the natural disappearance of malignant tumors, is rare. Little is known about the mechanisms underlying SR; however, immunological reactions, infections, injuries, and medications have been presumed. Among previously reported cases of SR, lung cancer cases have been extremely limited. Case Report: Here, we present a case of lymph node metastasis exacerbation after SR of a primary adenocarcinoma following a biopsy. After complete disappearance of the primary site tumor, metastatic lymph nodes in the mediastinum gradually increased in size as a single lesion. Local treatment with resection and radiotherapy was effective for this metastasis, without recurrence for >3 years. Conclusion: This is an interesting case of SR of pulmonary adenocarcinoma with inconsistent features in the primary and metastatic lesions. When physicians encounter exacerbation of metastatic sites with SR of the primary site in lung cancer, local intervention may be considered as a curative treatment.
Spontaneous regression (SR) of cancer, which is complete or partial disappearance of malignant tumors without any treatment, is an extremely rare phenomenon (1). Although this phenomenon has been described in different types of cancer, few cases involving lung cancer have been reported, and it is rarer in non-small-cell lung cancer (NSCLC) than in other cancers (2-5).
Little is known about the detailed mechanism of SR in cancer; it is poorly understood due to multiple factors, such as immunological imbalance for cancer progression, hormonal changes, infections, or operative trauma (5-7). Recently, several researchers reported SR in NSCLC after biopsy (5, 8-11). A possible explanation for this is that biopsy using endoscopic forceps may trigger the release of antigens with consequent activation of the immune system (5, 8-11). Furthermore, two recent reports have described the exacerbation of lymph node metastasis after SR of NSCLC. The mechanism of SR in cancer appears to differ between primary and metastatic sites (11, 12). Here, we present a case of lymph node metastasis exacerbation after SR of a primary adenocarcinoma following biopsy. All procedures involving human participants performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient provided informed consent for publication of this case report.
Case Report
A 77-year-old male with a history of smoking was treated with oral medications for diabetes mellitus and hyperlipidemia at a different clinic. Computed tomography (CT) was performed during a medical examination, and a small nodule in the left lower lobe was incidentally detected (Figure 1A). A follow-up radiographic examination was also performed. A CT scan performed after eight months showed gradual growth of this nodule to a diameter of 15 mm (Figure 1B), suggesting the presence of adenocarcinoma in the left subclavian lymph node (Figure 2A). Two-deoxy-2-[fluorine-18]-fluoro-D-glucose (18F-FDG) positron emission tomography (PET) revealed increased accumulation in the left subclavian lymph node and a small node in the left lower lobe, with a maximal standardized uptake value (SUVmax) of 1.9 (Figure 3A). Blood testing and physical findings were unremarkable, and there was no significant elevation of tumor markers. Diagnostic transbronchial biopsy was performed on the small node in the left lower lobe, and pathological examination revealed a definitive diagnosis of pulmonary adenocarcinoma. One month after the definitive diagnosis, a repeat CT scan was performed for the malignant potential of the left subclavian lymph node, which showed marked shrinking of the primary site (Figure 1C) and growth of the left subclavian lymph node (Figure 2B). Therefore, an observational examination was chosen at the patient’s request, and a subsequent CT scan revealed complete disappearance of the primary tumor (Figure 1D). 18F-FDG PET was performed 6 months after the initial diagnosis, and showed evidence of increased uptake in the left subclavian lymph node and no increased accumulation at the primary site (Figure 3B). Therefore, complete resection of the left subclavian lymph node (25×10 mm) for definite diagnosis revealed metastasis from the primary site. However, a new lymph node metastasis (13 mm) next to the completely resected lesion appeared on a follow-up CT scan one month after resection, unlike the outcome of the primary site (Figure 2C). There was no evidence of any genetic alterations, such as epidermal growth factor receptor (EGFR) or anaplastic large-cell lymphoma kinase (ALK) rearrangement, and programmed death-ligand 1 (PD-L1) immunostaining (22C3) showed high PD-L1 expression, with a tumor proportion score of 55%. Radiotherapy with a total dose of 66 Gy was initiated for the new lesion in the lymph node metastasis. Three years after the initial diagnosis of primary adenocarcinoma, there was no evidence of recurrence on follow-up radiological examination, with post-radiation pneumonitis (Figure 2D).
Chest computed tomography (CT) scan shows small nodule (white arrow) in the left lower lobe (A). Eight months later, the small nodule (white arrow) increased from 10 mm to 15 mm in diameter (B). The primary tumor (white arrow) markedly shrunk from 15 mm to 10 mm after one month (C). Subsequent CT scan exhibited a complete disappearance of the primary tumor (white arrow) (D).
Chest computed tomography (CT) scan in pulmonary apex shows the left subclavian lymph node (white arrow) (A). Six months later, the left subclavian lymph node increased in size (B). One month after the resection of this lymph node, a new lymph node (13 mm) (white arrow) next to the resected lesion appeared (C). After radiotherapy, there was no evidence of recurrence (white arrow) of lymph node metastasis with mild radiation pneumonitis (yellow arrow) (D).
Two-deoxy-2-[fluorine-18]-fluoro-d-glucose (18F-FDG) positron emission tomography (PET) (18F-FDG PET) imaging reveals increased uptake in the left subclavian lymph node with SUVmax of 3.4 (white arrow, upper column) and a small node in the lower left lobe with SUVmax of 1.9 (yellow arrow, lower column) (A). Six months after initial diagnosis, 18F-FDG PET shows increased accumulation on the left subclavian lymph node with SUVmax of 9.3 (white arrow, upper column) and no increased accumulation at the primary site (yellow arrow, lower column) (B).
Discussion
This is a unique case presenting the growth of metastatic lesion despite the SR of the primary site in lung cancer. We found two cases similar to our patient in previous studies (11, 12). One patient experienced enlargement of the subcarinal lymph node 33 months after SR of primary squamous cell carcinoma (11), and the other exhibited an inconsistent course with the progression of metastatic 4R lymph nodes 6 weeks after partial SR of primary squamous cell carcinoma (SCC) (12). Although it remains unclear whether both primary and metastatic sites regress simultaneously in the majority of SR cases, certain biological mechanisms may differ between primary and metastatic lesions, as in our case. In the present case, metastatic sites without SR were treated with local therapy, including surgical resection and radiotherapy, and curative outcomes were successfully achieved. Generally, metastatic lesions due to primary lung cancer should be treated with systemic therapy because of the presence of tumor micrometastases. In the previous two cases of SR at the primary site, metastatic lesions were also managed by surgical treatment (11, 12). If there is a discrepancy in the SR between the primary and metastatic sites, the exacerbating sites may be controlled as much as possible by local treatment without systemic therapy.
A previous report stated that 40% of SR cases are associated with tissue destruction, such as operative trauma, which causes immunological stimulation (1). Fever, infection, injury, and medication have been clinically postulated to be among the mechanisms of SR (13); however, our patient did not have any reason except for injury by biopsy. Twenty-three cases of SR of lung cancer have been previously reported in the literature; these histological types included SCC in seven patients, small cell lung carcinoma (SCLC) in eight patients, NSCLC in two patients, adenocarcinoma in four patients, and large cell carcinoma in two patients (5, 8-18). Most SR of lung cancer were identified as SCC or SCLC without an underlying reason. Of these cases, two patients had high expression of PD-L1>50% with a histology of SCC, and one patient had an adenocarcinoma with an EGFR mutation. PD-L1 expression and genetic alterations were not evaluated except in recent cases. Therefore, it remains unclear whether genetic alterations or the tumor immune environment affect the oncological phenomenon of SR in lung cancer. Further studies are warranted to elucidate the underlying mechanisms of SR with respect to the tumor immune environment and genetic approaches. If physicians encounter exacerbation of metastatic sites with SR of the primary site in lung cancer, local intervention may be considered a curative treatment. Systemic therapy should be recommended in cases of distant expansion of metastatic sites.
Footnotes
Authors’ Contributions
KK conceived the study and drafted and critically revised the article. H.I. OY, AM, and HK acquired, analyzed, and interpreted the data and critically revised the article.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
Funding
This research received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors.
- Received January 8, 2024.
- Revision received February 5, 2024.
- Accepted February 6, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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