Spontaneous remission of advanced progressive poorly differentiated non-small cell lung cancer: a case report and review of literature
Spontaneous remission (SR) of cancer is a very rare phenomenon of unknown mechanism. In particular, SR of non-small cell lung cancer (NSCLC) has been scarcely reported. We present the case of a 74-year-old woman with advanced, poorly differentiated NSCLC (highly expressing programmed death ligand-1 [PD-L1]) that progressed despite multiple lines of chemotherapy but then spontaneously remitted.
The patient presented with hemoptysis and was diagnosed with stage IIIA poorly differentiated NSCLC via bronchoscopic biopsy. She had an unremarkable medical history and moderate performance status. The initial treatment plan was surgery after neoadjuvant chemotherapy. Despite conventional chemotherapy, follow-up chest computed tomography (CT) showed gradual tumor progression and she decided against further treatment after fifth-line chemotherapy. However, the size of lung mass was markedly decreased on follow-up chest CT one year after ceasing chemotherapy. Also, follow-up positron emission tomography images showed decreased metabolic activity in the lung mass and a percutaneous biopsy specimen from the diminished lung mass revealed no viable tumor cells. A diagnosis of SR of NSCLC was confirmed, and the patient was without tumor progression on follow-up nine months later. Later, PD-L1 immunostaining revealed high positivity (> 99%) in initial tumor cells.
Our case showing SR of poorly advanced NSCLC refractory to multiple lines of chemotherapy suggested the association between immunity and tumor regression.
KeywordsAdvanced stage Chemotherapy Prognosis Immunity Disease progression
Non-small cell lung cancer
Programmed death ligand-1
Positron emission tomography/computed tomography
Spontaneous remission (SR) of cancer is defined as partial or complete disappearance of a malignant tumor without any standard treatment or with inadequate treatment for cancer control. Cole and Everson first reported 47 cases of biopsy-confirmed SR of cancer, proposing the term and criteria for SR in 1956 . Although neuroblastoma, bladder cancer, and lymphoma have shown relatively high incidences of SR , SR of non-small cell lung cancer (NSCLC) is rare, with only a few cases reported worldwide [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. Here, we present a case of a 74-year-old woman diagnosed with advanced poorly differentiated NSCLC that spontaneously remitted after failure of multiple courses of chemotherapy.
After brain magnetic resonance imaging for cancer staging, which revealed a non-metastatic lesion, a tentative diagnosis of lung cancer with T3N1M0 (stage IIIA according to TNM seventh edition) was proposed. At first, the patient planned to undergo surgery after two cycles of paclitaxel plus carboplatin as neoadjuvant chemotherapy, inducing a decrease in the size of the lung mass from 5.1 × 2.9 cm to 4.1 × 1.5 cm. However, the patient developed drug-induced hepatitis with aspartate aminotransferase (AST) / alanine aminotransferase (ALT) of 110 / 182 IU/L due to a self-prescribed herbal medication, and the surgery schedule was delayed. For two weeks, waiting for the AST / ALT levels to drop, the lung mass slightly increased (4.1 × 2.6 cm), and she hesitated to undergo surgery. So afterwards she received additional two cycles of paclitaxel plus carboplatin, which means that she received a total of four cycles of paclitaxel plus carboplatin. However, the tumor still progressed, and fifth-line chemotherapy was sequentially administered until the fifth-line as follows: second-line for 4 cycles of gemcitabine plus carboplatin, third-line for 2 cycles of pemetrexed, fourth-line for 4 cycles of weekly docetaxel, fifth-line for 1 cycle of weekly vinorelbine. After a vinorelbine monotherapy, the patient refused further chemotherapy due to general weakness. At 4 months after discontinuation of chemotherapy, the size of the tumor on follow-up chest x-ray (Fig. 1-c) and CT (Fig. 1-d) was markedly increased (6.8 × 6.0 cm), directly invading left main pulmonary artery, left atrium, and left lower lobe. Thus, the patient again started irinotecan plus carboplatin as sixth-line chemotherapy. Although tumor size decreased after 4 cycles of chemotherapy, she decided to stop chemotherapy due to poor general condition and drug side effects and was scheduled for regular follow-up for tumor surveillance.
One year after discontinuation of treatment, a chest x-ray showed that the lung mass had decreased in size (Fig. 1-e). The patient had been taking herbal medication (Orostachys japonicus extracts) over the preceding few months. Chest CT taken during admission for disease status re-evaluation revealed the lung mass in the left lingular segment to have decreased in size to 3.6 × 2.5 cm (Fig. 1-f). PET/CT also demonstrated decreased size and metabolic activity of the lung mass (Figs. 2-c and d) and hilar lymph node. For further treatment planning, we performed bronchoscopy and intended repeat tumor biopsy, but only found fibrotic scar blocking the ligular segment instead of an endobronchial mass (Fig. 3-b). Histologic examination of the second bronchoscopic biopsy revealed chronic inflammation with foamy histiocytic infiltration (Fig. 4c). We subsequently conducted fluoroscopy-guided lung biopsy of the left lung mass. Percutaneous needle biopsy of the left lung lesion showed marked deposition of collagen and elastic fibers without tumor cells. (Fig. 4d). The histopathologic findings of second bronchoscopic biopsy and percutaneous lung needle biopsy were suggestive of tumor regression.
A diagnosis of SR of NSCLC was made, and the patient was without cancer progression on outpatient clinic follow-up at 9 months after the detection of SR.
Discussion and conclusion
Literature review of spontaneous remission of histologically confirmed non-small cell lung cancer
Herbal remedy after ceasing multiple line chemotherapy
Matsui et al. 2018 *
CTD-ILD and autoimmune hepatitis
Ooi et al. 2018 
Marques et al. 2017 
COPD, heart failure
Park et al. 2016 
Chung et al. 2015 
Chemotherapy and herbal remedy
Ogawa et al. 2015 
Menon et al. 2015 
None except HAART on combined HIV infection
Lopez-Pastorini et al. 2015 
Hwang et al. 2013 
Mizuno et al. 2011 
None after surgery for initially stage I lung cancer
Furukawa et al. 2011 
Gladwish et al. 2010 
Herbal remedy (Essiac tea)
Nakamura et al. 2009 
Anti-NY-ESO-1 immunity disease
Pujol et al. 2007 
Anti-Hu antibody syndrome, diabetes
Cafferata et al. 2004 
COPD, ischemic heart disease
Kappauf et al. 1997 
Sperduto et al. 1988 
COPD, basal cell cancer
The mechanism of SR remains unclear. Interestingly, poorly differentiated cancer is common among the reported cases of SR in patients with NSCLC. Light microscopy alone may be insufficient to diagnose poorly differentiated carcinoma, which has been reported to have a poor prognosis [21, 22]. The diagnosis of poorly differentiated carcinoma depends substantially on additional pathologist’s interpretation and adequate specimen size. The finding that many SR cases involved tumors showing poorly differentiated features despite testing with recently developed novel immunochemical markers suggests that the cancers of origin might have been misclassified. In addition, poorly differentiated NCLC has higher fluorodeoxyglucose (FDG) uptake at positron emission tomography and Ki-67 proliferation index compared with well-differentiated NSCLC . Also, there have been several cases of poorly differentiated lung cancer accompanied by leukemoid reaction [24, 25, 26]. Inflammation is physiologically self-limiting; acute inflammation is terminated by activated neutrophils generating specialized pro-resolving mediators (SPM), including lipoxins, resolvins, protectins, and maresins, which are derived from essential fatty acids [27, 28]. There is in vitro evidence that SPM controls both innate and adaptive immunity by reducing the production of inflammatory cytokines (e.g., tumor necrosis factor-alpha and interferon-gamma) and memory B-cell antibody production [29, 30]. Considering the association between cancer progression and inflammation, increased cellular proliferation in poorly differentiated carcinoma might paradoxically induce the suppression of tumor growth via SPM, resulting in SR of cancer.
Unlike most other reported SR cases, which involved smokers, our patient was a non-smoker. Several studies recently reported superior efficacy of immunotherapy in smokers compared with non-smokers but did not clarify the mechanism of this effect . Also, strong PD-L1 positivity and presence of tumor infiltrating lymphocytes (TIL), which are predictive biomarkers for immunotherapy , were identified in this case. Taken together, our findings and the results of previous studies support the association between immunity and cancer control.
Our patient was taking herbal medication (Orostachys japonicus extracts) after the discontinuation of chemotherapy. Gladwish et al. reported the case of a patient with SR of stable IIB NSCLC after receiving an herbal remedy (essiac tea) , which shows an antiproliferative effect on cancer cells at high concentration in vitro . Chung et al. also reported the case of a patent with SR of NSCLC who took herbal medication during and after chemotherapy . Orostachys japonicus is a flowering plant, containing several organic solvents including ethyl acetate with anti-cancer effects on human gastric cancer cells . An in vivo model study also suggests the role of Orostachys japonicus in enhancing immunity by increasing immune cell propagation and production of immunity-related cytokines . In our case, the tumor had many TIL and high PD-L1 expression, indicating that the patient had an antitumor immune response and had been eligible for treatment with an immune checkpoint inhibitor. Although no data are available to demonstrate the efficacy of Orostachys japonicus in humans, SR in our cases might be influenced by Orostachys japonicus intake.
Because our patient had received multiple cycles of chemotherapy before the occurrence of SR, there was a possibility of pseudo-progression or delayed response to chemotherapy. However, the chemotherapy regimen had changed several times, and tumor regression was observed one year after the last treatment, suggesting a high probability of SR. In addition, all of the chemotherapeutic agents administered to our patient would be less likely to show pseudo-progression because they are conventional drugs rather than immune checkpoint inhibitors.
In conclusion, we document a case of SR in a patient with advanced NSCLC refractory to conventional chemotherapy. Although the precise mechanism of SR in this case is unknown, the alteration of immunity might be an explanation. A single case cannot lead to a definite conclusion; nevertheless, our case indicates the importance of immunity in lung cancer control. Further well-designed animal model studies are needed to explore these findings.
J.H.L. had the conception of the work. H.Y.Y. drafted the manuscript. J.H.L. substantively revised it. Y.K.K. and S.S.S interpreted radiological findings and H.S.P. and M.S.C interpreted pathological findings. All authors approved the submitted version and agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
The corresponding author, J.H.R received National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2010–0027945) for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Ethics approval and consent to participate
Consent for publication
A written informed consent was obtained from the patient for publication of this report and any accompanying images.
The authors declare that they have no competing interests.
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